Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels

ABSTRACT

The invention relates to heterocyclic chromene-spirocyclic piperidine amides useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119 to U.S.provisional patent application Ser. Nos. 61/331,882, filed May 6, 2010;and 61/438,688, filed Feb. 2, 2011, the entire contents of allapplications are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The invention relates to compounds useful as inhibitors of ion channels.The invention also provides pharmaceutically acceptable compositionscomprising the compounds of the invention and methods of using thecompositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Pain is a protective mechanism that allows healthy animals to avoidtissue damage and to prevent further damage to injured tissue.Nonetheless there are many conditions where pain persists beyond itsusefulness, or where patients would benefit from inhibition of pain.Voltage-gated sodium channels are believed to play a critical role inpain signaling. This belief is based on the known roles of thesechannels in normal physiology, pathological states arising frommutations in sodium channel genes, preclinical work in animal models ofdisease, and the clinical usefulness of known sodium channel modulatingagents (Cummins, T. R., Sheets, P. L., and Waxman, S. G., The roles ofsodium channels in nociception: Implications for mechanisms of pain.Pain 131 (3), 243 (2007); England, S., Voltage-gated sodium channels:the search for subtype-selective analgesics. Expert Opin Investig Drugs17 (12), 1849 (2008); Krafte, D. S, and Bannon, A. W., Sodium channelsand nociception: recent concepts and therapeutic opportunities. CurrOpin Pharmacol 8 (1), 50 (2008)).

Voltage-gated sodium channels (NaV's) are key biological mediators ofelectrical signaling. NaV's are the primary mediators of the rapidupstroke of the action potential of many excitable cell types (e.g.neurons, skeletal myocytes, cardiac myocytes), and thus are critical forthe initiation of signaling in those cells (Hille, Bertil, Ion Channelsof Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland,Mass., 2001)). Because of the role NaV's play in the initiation andpropagation of neuronal signals, antagonists that reduce NaV currentscan prevent or reduce neural signaling. Thus NaV channels are consideredlikely targets in pathologic states where reduced excitability ispredicted to alleviate the clinical symptoms, such as pain, epilepsy,and some cardiac arrhythmias (Chahine, M., Chatelier, A., Babich, O.,and Krupp, J. J., Voltage-gated sodium channels in neurologicaldisorders. CNS Neurol Disord Drug Targets 7 (2), 144 (2008)).

The NaV's form a subfamily of the voltage-gated ion channel super-familyand comprises 9 isoforms, designated NaV 1.1-NaV 1.9. The tissuelocalizations of the nine isoforms vary greatly. NaV 1.4 is the primarysodium channel of skeletal muscle, and NaV 1.5 is primary sodium channelof cardiac myocytes. NaV's 1.7, 1.8 and 1.9 are primarily localized tothe peripheral nervous system, while NaV's 1.1, 1.2, 1.3, and 1.6 areneuronal channels found in both the central and peripheral nervoussystems. The functional behaviors of the nine isoforms are similar butdistinct in the specifics of their voltage-dependent and kineticbehavior (Catterall, W. A., Goldin, A. L., and Waxman, S. G.,International Union of Pharmacology. XLVII. Nomenclature andstructure-function relationships of voltage-gated sodium channels.Pharmacol Rev 57 (4), 397 (2005)).

NaV channels have been identified as the primary target for someclinically useful pharmaceutical agents that reduce pain (Cummins, T.R., Sheets, P. L., and Waxman, S. G., The roles of sodium channels innociception: Implications for mechanisms of pain. Pain 131 (3), 243(2007)). The local anesthetic drugs such as lidocaine block pain byinhibiting NaV channels. These compounds provide excellent local painreduction but suffer the drawback of abolishing normal acute pain andsensory inputs. Systemic administration of these compounds results indose limiting side effects that are generally ascribed to block ofneural channels in the CNS (nausea, sedation, confusion, ataxia).Cardiac side effects can also occur, and indeed these compounds are alsoused as class 1 anti-arrhythmics, presumably due to block of NaV 1.5channels in the heart. Other compounds that have proven effective atreducing pain have also been suggested to act by sodium channel blockadeincluding carbamazepine, lamotragine, and tricyclic antidepressants(Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action.Eur J Pain 6 Suppl A, 3 (2002); Wang, G. K., Mitchell, J., and Wang, S.Y., Block of persistent late Na+ currents by antidepressant sertralineand paroxetine. J Membr Biol 222 (2), 79 (2008)). These compounds arelikewise dose limited by adverse effects similar to those seen with thelocal anesthetics. Antagonists that specifically block only theisoform(s) critical for nocioception are expected to have increasedefficacy since the reduction of adverse effects caused by block ofoff-target channels should enable higher dosing and thus more completeblock of target channels isoforms.

Four NaV isoforms, NaV 1.3, 1.7, 1.8, and 1.9, have been specificallyindicated as likely pain targets. NaV 1.3 is normally found in the painsensing neurons of the dorsal root ganglia (DRG) only early indevelopment and is lost soon after birth both in humans and in rodents.Nonetheless, nerve damaging injuries have been found to result in areturn of the NaV 1.3 channels to DRG neurons and this may contribute tothe abnormal pain signaling in various chronic pain conditions resultingfrom nerve damage (neuropathic pain). These data have led to thesuggestion that pharmaceutical block of NaV 1.3 could be an effectivetreatment for neuropathic pain. In opposition to this idea, globalgenetic knockout of NaV 1.3 in mice does not prevent the development ofallodynia in mouse models of neuropathic pain (Nassar, M. A. et al.,Nerve injury induces robust allodynia and ectopic discharges in NaV 1.3null mutant mice. Mol Pain 2, 33 (2006)). It remains unknown whethercompensatory changes in other channels allow for normal neuropathic painin NaV 1.3 knockout mice, though it has been reported that knockout ofNaV 1.1 results in drastic upregulation of NaV 1.3. The converse effectin NaV 1.3 knockouts might explain these results.

NaV 1.7, 1.8, and 1.9 are highly expressed in DRG neurons, including theneurons whose axons make up the C-fibers and Aδ nerve fibers that arebelieved to carry most pain signals from the nocioceptive terminals tothe central nervous. Like NaV 1.3, NaV 1.7 expression increases afternerve injury and may contribute to neuropathic pain states. Thelocalization of NaV 1.7, 1.8, and 1.9 in nocioceptors led to thehypothesis that reducing the sodium currents through these channelsmight alleviate pain. Indeed, specific interventions that reduce thelevels of these channels have proven effective in animal models of pain.

Specific reduction of NaV 1.7 in rodents by multiple differenttechniques has resulted in the reduction of observable pain behaviors inmodel animals. Injection of a viral antisense NaV 1.7 cDNA constructgreatly reduces normal pain responses due to inflammation or mechanicalinjury (Yeomans, D. C. et al., Decrease in inflammatory hyperalgesia byherpes vector-mediated knockdown of NaV 1.7 sodium channels in primaryafferents. Hum Gene Ther 16 (2), 271 (2005)). Likewise, a geneticknockout of NaV 1.7 in a subset of nociceptor neurons reduced acute andinflammatory pain in mouse models (Nassar, M. A. et al.,Nociceptor-specific gene deletion reveals a major role for NaV 1.7 (PN1)in acute and inflammatory pain. Proc Natl Acad Sci USA 101 (34), 12706(2004)). Global knockouts of NaV 1.7 in mice lead to animals that die onthe first day after birth. These mice fail to feed and this is thepresumed cause of death.

Treatments that specifically reduce NaV 1.8 channels in rodent modelseffectively reduce pain sensitivity. Knockdown of NaV 1.8 in rats byintrathecal injection of antisense oligodeoxynucleotides reducesneuropathic pain behaviors, while leaving acute pain sensation intact(Lai, J. et al., Inhibition of neuropathic pain by decreased expressionof the tetrodotoxin-resistant sodium channel, NaV1.8. Pain 95 (1-2), 143(2002); Porreca, F. et al., A comparison of the potential role of thetetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in ratmodels of chronic pain. Proc Natl Acad Sci USA 96 (14), 7640 (1999)).Global genetic knockout of NaV 1.8 in mice or specific destruction ofNaV 1.8 expressing neurons greatly reduces perception of acutemechanical, inflammatory, and visceral pain (Akopian, A. N. et al., Thetetrodotoxin-resistant sodium channel SNS has a specialized function inpain pathways. Nat Neurosci 2 (6), 541 (1999); Abrahamsen, B. et al.,The cell and molecular basis of mechanical, cold, and inflammatory pain.Science 321 (5889), 702 (2008); Laird, J. M., Souslova, V., Wood, J. N.,and Cervero, F., Deficits in visceral pain and referred hyperalgesia inNaV 1.8 (SNS/PN3)-null mice. J Neurosci 22 (19), 8352 (2002)). Incontrast to the antisense experiments in rats, genetic knockout miceappear to develop neuropathic pain behaviors normally after nerve injury(Lai, J. et al., Inhibition of neuropathic pain by decreased expressionof the tetrodotoxin-resistant sodium channel, NaV1.8. Pain 95 (1-2), 143(2002); Akopian, A. N. et al., The tetrodotoxin-resistant sodium channelSNS has a specialized function in pain pathways. Nat Neurosci 2 (6), 541(1999); Abrahamsen, B. et al., The cell and molecular basis ofmechanical, cold, and inflammatory pain. Science 321 (5889), 702 (2008);Laird, J. M., Souslova, V., Wood, J. N., and Cervero, F., Deficits invisceral pain and referred hyperalgesia in NaV 1.8 (SNS/PN3)-null mice.J Neurosci 22 (19), 8352 (2002)).

NaV 1.9 global knock out mice have decreased sensitivity to inflammationinduced pain, despite normal acute, and neuropathic pain behaviors(Amaya, F. et al., The voltage-gated sodium channel Na(v)1.9 is aneffector of peripheral inflammatory pain hypersensitivity. J Neurosci 26(50), 12852 (2006); Priest, B. T. et al., Contribution of thetetrodotoxin-resistant voltage-gated sodium channel NaV 1.9 to sensorytransmission and nociceptive behavior. Proc Natl Acad Sci USA 102 (26),9382 (2005)). Spinal knockdown of NaV 1.9 had no apparent effect on painbehavior in rats (Porreca, F. et al., A comparison of the potential roleof the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2,in rat models of chronic pain. Proc Natl Acad Sci USA 96 (14), 7640(1999)).

The understanding of the role of NaV channels in human physiology andpathology has been greatly advanced by the discovery and analysis ofnaturally occurring human mutations. NaV 1.1 and NaV 1.2 mutationsresult in various forms of epilepsy (Fujiwara, T., Clinical spectrum ofmutations in SCN1A gene: severe myoclonic epilepsy in infancy andrelated epilepsies. Epilepsy Res 70 Suppl 1, S223 (2006); George, A. L.,Jr., Inherited disorders of voltage-gated sodium channels. J Clin Invest115 (8), 1990 (2005); Misra, S. N., Kahlig, K. M., and George, A. L.,Jr., Impaired NaV1.2 function and reduced cell surface expression inbenign familial neonatal-infantile seizures. Epilepsia 49 (9), 1535(2008)). Mutations of the NaV 1.4 cause muscular disorders likeparamyotonia congenital (Vicart, S., Sternberg, D., Fontaine, B., andMeola, G., Human skeletal muscle sodium channelopathies. Neurol Sci 26(4), 194 (2005)). NaV 1.5 mutations result in cardiac abnormalities likeBrugada Syndrome and long QT syndrome (Bennett, P. B., Yazawa, K.,Makita, N., and George, A. L., Jr., Molecular mechanism for an inheritedcardiac arrhythmia. Nature 376 (6542), 683 (1995); Darbar, D. et al.,Cardiac sodium channel (SCN5A) variants associated with atrialfibrillation. Circulation 117 (15), 1927 (2008); Wang, Q. et al., SCN5Amutations associated with an inherited cardiac arrhythmia, long QTsyndrome. Cell 80 (5), 805 (1995)).

Recent discoveries have demonstrated that mutations in the gene thatencodes the NaV 1.7 channel (SCN9A) can cause both enhanced and reducedpain syndromes. Work by Waxman's group and others have identified atleast 15 mutations that result in enhanced current through NaV 1.7 andare linked to dominant congenital pain syndromes. Mutations that lowerthe threshold for NaV 1.7 activation cause inherited erythromelalgia(IEM). IEM patients exhibit abnormal burning pain in their extremities.Mutations that interfere with the normal inactivation properties of NaV1.7 lead to prolonged sodium currents and cause paroxysmal extreme paindisorder (PEPD). PEPD patients exhibit periocular, perimandibular, andrectal pain symptoms that progresses throughout life (Drenth, J. P. etal., SCN9A mutations define primary erythermalgia as a neuropathicdisorder of voltage gated sodium channels. J Invest Dermatol 124 (6),1333 (2005); Estacion, M. et al., NaV 1.7 gain-of-function mutations asa continuum: A1632E displays physiological changes associated witherythromelalgia and paroxysmal extreme pain disorder mutations andproduces symptoms of both disorders. J Neurosci 28 (43), 11079 (2008)).

NaV 1.7 null mutations in human patients were recently described byseveral groups (Ahmad, S. et al., A stop codon mutation in SCN9A causeslack of pain sensation. Hum Mol Genet. 16 (17), 2114 (2007); Cox, J. J.et al., An SCN9A channelopathy causes congenital inability to experiencepain. Nature 444 (7121), 894 (2006); Goldberg, Y. P. et al.,Loss-of-function mutations in the NaV 1.7 gene underlie congenitalindifference to pain in multiple human populations. Clin Genet. 71 (4),311 (2007)). In all cases patients exhibit congenital indifference topain. These patients report no pain under any circumstances. Many ofthese patients suffer dire injuries early in childhood since they do nothave the protective, normal pain that helps to prevent tissue damage anddevelop appropriate protective behaviors. Aside from the striking lossof pain sensation and reduced or absent of smell (Goldberg, Y. P. etal., Loss-of-function mutations in the NaV 1.7 gene underlie congenitalindifference to pain in multiple human populations. Clin Genet. 71 (4),311 (2007)), these patients appear completely normal. Despite thenormally high expression of NaV 1.7 in sympathetic neurons (Toledo-Aral,J. J. et al., Identification of PN1, a predominant voltage-dependentsodium channel expressed principally in peripheral neurons. Proc NatlAcad Sci USA 94 (4), 1527 (1997)) and adrenal chromafin cells(Klugbauer, N., Lacinova, L., Flockerzi, V., and Hofmann, F., Structureand functional expression of a new member of the tetrodotoxin-sensitivevoltage-activated sodium channel family from human neuroendocrine cells.EMBO J. 14 (6), 1084 (1995)), these NaV 1.7-null patients show no signof neuroendocrine or sympathetic nervous dysfunction.

The gain of NaV 1.7 function mutations that cause pain, coupled with theloss of NaV 1.7 function mutations that abolish pain, provide strongevidence that NaV 1.7 plays an important role in human pain signaling.The relative good health of NaV 1.7-null patients indicates thatablation of NaV 1.7 is well tolerated in these patients.

Unfortunately, the efficacy of currently used sodium channel blockersfor the disease states described above has been to a large extentlimited by a number of side effects. These side effects include variousCNS disturbances such as blurred vision, dizziness, nausea, and sedationas well more potentially life threatening cardiac arrhythmias andcardiac failure. Accordingly, there remains a need to develop additionalNa channel antagonists, preferably those with higher potency and fewerside effects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are useful asinhibitors of voltage-gated sodium channels. These compounds have thegeneral formula I:

or a pharmaceutically acceptable salt thereof.

These compounds and pharmaceutically acceptable compositions are usefulfor treating or lessening the severity of a variety of diseases,disorders, or conditions, including, but not limited to, acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders such as anxiety and depression, myotonia,arrhythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, incontinence, visceralpain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, or cancer pain.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence and optionally substituted asvalency allows:

-   R¹ is C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH,    OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷,    CON(R⁷)₂, SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl,    heteroaryl or (C1-C6)-R⁸ wherein up to two CH₂ units may be replaced    with O, CO, S, SO, SO₂, or NR⁷;-   R² is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, aryl,    an electron withdrawing group, OR⁷, CH₂CF₃, CHF₂, CF₃, CN, CON(R⁷)₂,    SO₂R⁷, SR⁷, SOR⁷, SO₂N(R⁷)₂, or (C1-C6)-R⁸ wherein up to two CH₂    units may be replaced with O, CO, S, SO, SO₂, CF₂, or NR⁷;-   R³ is halo, C1-C6 alkyl or C3-C8 cycloalkyl, wherein up to two CH₂    units may be replaced by O, CO, S, SO, SO₂, or NR⁸, or 2 occurrences    of R³ taken together form a C3-C8 cycloalkyl group;-   R⁷ is H, C1-C6 alkyl, CHF₂, CF₃, or C3-C8 cycloalkyl, or 2 R⁷ taken    together with the atoms to which they are attached form a ring;-   R⁸ is H, CF₃, CO₂R⁷, OH, aryl, heteroaryl, C3-C8 cycloalkyl,    heterocycloalkyl, N(R⁷)₂, NR⁷COR⁷, CON(R⁷)₂, CN, or SO₂R⁷;    A is aryl, heteroaryl or heterocyclic;    X is N, S, or CR² wherein at least one X is N;    W is N or CH, wherein up to 2 W are N;    a ---- line denotes an optionally double bond depending on the    identity of X;    m is an integer from 0 to 4 inclusive;    n is an integer from 0 to 3 inclusive; and    o is an integer from 0 to 4 inclusive.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry”, 5^(th), Ed.: Smith, M. B. and March, J.,John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, compounds of the invention can optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. The phrase “optionally substituted” isused interchangeably with the phrase “substituted or unsubstituted.” Asdescribed herein, the variables R¹-R⁸ in formula I encompass specificgroups, such as, for example, alkyl and aryl. Unless otherwise noted,each of the specific groups for the variables R¹-R⁸ can be optionallysubstituted with one or more substituents of halo, cyano, oxoalkoxy,hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. For instance, analkyl group can be optionally substituted with one or more of halo,cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. Asan additional example, an aryl group can be optionally substituted withone or more of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, andalkyl. As one of ordinary skill in the art will recognize, combinationsof substituents envisioned by this invention are those combinations thatresult in the formation of stable or chemically feasible compounds. Theterm “stable”, as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and preferably their recovery, purification, anduse for one or more of the purposes disclosed herein. In someembodiments, a stable compound or chemically feasible compound is onethat is not substantially altered when kept at a temperature of 40° C.or less, in the absence of moisture or other chemically reactiveconditions, for at least a week. When two alkoxy groups are bound to thesame atom or adjacent atoms, the two alkoxy groups can form a ringtogether with the atom(s) to which they are bound.

In general, the term “substituted,” whether preceded by the term“optionally” or not, refers to the replacement of hydrogen radicals in agiven structure with the radical of a specified substituent. Specificsubstituents are described above in the definitions and below in thedescription of compounds and examples thereof. Unless otherwiseindicated, an optionally substituted group can have a substituent ateach substitutable position of the group, and when more than oneposition in any given structure can be substituted with more than onesubstituent selected from a specified group, the substituent can beeither the same or different at every position. A ring substituent, suchas a heterocycloalkyl, can be bound to another ring, such as acycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings shareone common atom. As one of ordinary skill in the art will recognize,combinations of substituents envisioned by this invention are thosecombinations that result in the formation of stable or chemicallyfeasible compounds.

The phrase “up to”, as used herein, refers to zero or any integer numberthat is equal or less than the number following the phrase. For example,“up to 3” means any one of 0, 1, 2, and 3.

The term “aliphatic”, “aliphatic group” or “alkyl” as used herein, meansa straight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation. Unless otherwise specified,aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms, and in yet other embodi ments aliphatic groups contain 1-4aliphatic carbon atoms. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, alkynyl groups. The term “cycloaliphatic” or “cycloalkyl” meana monocyclic hydrocarbon, bicyclic, or tricyclic hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic and has a single point of attachment to therest of the molecule. In some embodiments, “cycloaliphatic” refers to amonocyclic C₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic, that has a single point of attachment to therest of the molecule wherein any individual ring in said bicyclic ringsystem has 3-7 members.

The term “electron withdrawing group”, as used herein means an atom or agroup that is electronegative relative to hydrogen. See, e.g., “AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure,” Jerry March,4^(th) Ed., John Wiley & Sons (1992), e.g., pp. 14-16, 18-19, etc.Exemplary such substituents include halo such as Cl, Br, or F, CN, COOH,CF₃, etc.

Unless otherwise specified, the term “heterocycle”, “heterocyclyl”,“heterocycloaliphatic”, “heterocycloalkyl” or “heterocyclic” as usedherein means non-aromatic, monocyclic, bicyclic, or tricyclic ringsystems in which one or more ring atoms in one or more ring members isan independently selected heteroatom. Heterocyclic ring can be saturatedor can contain one or more unsaturated bonds. In some embodiments, the“heterocycle”, “heterocyclyl”, “heterocycloaliphatic”,“heterocycloalkyl” or “heterocyclic” group has three to fourteen ringmembers in which one or more ring members is a heteroatom independentlyselected from oxygen, sulfur, nitrogen, or phosphorus, and each ring inthe ring system contains 3 to 7 ring members.

The term “heteroatom” means oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus,or silicon; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation but is not aromatic.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring carbon atoms, wherein at least one ring in the system is aromaticand wherein each ring in the system contains 3 to 7 ring carbon atoms.The term “aryl” may be used interchangeably with the term “aryl ring”.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Thus, included within the scope of the invention aretautomers of compounds of formula I.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds of formulaI, wherein one or more hydrogen atoms are replaced deuterium or tritium,or one or more carbon atoms are replaced by a ¹³C- or ¹⁴C-enrichedcarbon are within the scope of this invention. Such compounds areuseful, for example, as analytical tools, probes in biological assays,or sodium channel blockers with improved therapeutic profile.

In the formulas and drawings, a line transversing a ring and bonded toan R group such as in

means that the R group can be bonded to any carbon, or if applicable,heteroatom such as N, of that ring as valency allows.

Within a definition of a term as, for example, R³, R⁴, R⁵, or R⁶, when aCH₂ unit or, interchangeably, methylene unit may be replaced by O, NR⁷,or S, it is meant to include any CH₂ unit, including a CH₂ within aterminal methyl group. For example, —CH₂CH₂CH₂SH is within thedefinition of C1-C6 alkyl wherein up to two CH₂ units may be replaced byS because the CH₂ unit of the terminal methyl group has been replaced byS.

In another embodiment, the invention relates to a compound of formula Iand the attendant definitions, wherein all W's are CH. In anotherembodiment, one W is N.

In another embodiment, the invention relates to a compound of formula Iand the attendant definitions, wherein R¹ is C1-C6 alkyl, C1-C6 alkoxy,halo, CN, CON(R⁷)₂, or (C1-C6)-R⁸ wherein up to two CH₂ units may bereplaced with O, CO, S, SO, SO₂, or NR⁷.

In another embodiment, R′ is F, Cl, CH₃, CN, OCH₃, CH₂OH, CH₂N(CH₃)₂,CH₂NH₂, CONHCH₃, CON(CH₃)₂, CH₂OCH₃.

In another embodiment, the invention relates to a compound of formula Iand the attendant definitions, wherein R² is C1-C6 alkyl,C1-C6-haloalkyl, halo, CN, OR⁷, CF₃, CON(R⁷)₂, SO₂R⁷, or (C1-C6)-R⁸wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂, orNR⁷. In another embodiment, R² is CH₃, CF₃, CHF₂, C₂H₅, CH₂OH, halo, CN,(CH₂)₂OCH₃, SO₂CH₃, SOCH₃, CH₂CF₃, CH₂NH₂, CH₂NHCOCH₃, CH₂NHCOH, COCH₃,or CONHCH₃.

In another embodiment, the invention relates to a compound of formula Iand the attendant definitions, wherein R³ is C1-C6 alkyl. In anotherembodiment, R³ is methyl. In another embodiment, 2 occurrences of R³taken together form a C3-C8 cycloalkyl group.

In another embodiment, the invention relates to a compound of formula Iand the attendant definitions, wherein m is 0, 1 or 2. In anotherembodiment, m is 0.

In another embodiment, the invention relates to a compound of formula Iand the attendant definitions, wherein n is 0, 1 or 2. In anotherembodiment, n is 0. In another embodiment, n is 1.

In another embodiment, o is 0.

In another embodiment, the invention relates to a compound of formula Iand the attendant definitions, wherein A is

wherein:

-   R⁴ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH,    OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷,    CON(R⁷)₂, SO₂N(R⁷)₂, CHF₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl,    heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R⁸    wherein up to three CH₂ units may be replaced with O, CO, S, SO,    SO₂, or NR⁷;-   R⁵ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8    cycloalkoxy, halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷,    CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂, SO₂N(R)₂, CF₃, OCF₃, OCHF₂,    heterocycloalkyl, aryl, heteroaryl, or a straight chain, branched,    or cyclic (C1-C8)-R⁸ wherein up to three CH₂ units may be replaced    with O, CO, S, SO, SO₂, or NR⁷;-   R⁶ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH,    OR⁷, N(R)₂, NR⁷SO₂R⁷, SR⁷, SOR⁷, SO₂R⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷,    CON(R⁷)₂, SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl,    heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R⁸    wherein up to three CH₂ units may be replaced with O, CO, S, SO,    SO₂, or NR⁷; or-   two occurrences of R⁴ and R⁵, or R⁵ and R⁶ are both C1-C6 alkyl and    together with the carbons to which they are attached form an    optionally substituted ring comprising up to 2 heteroatoms.

In another embodiment, R⁴ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH,OR⁷, CON(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, SOR⁷, SR⁷, CO₂R⁷, NR⁷CO₂R⁷, CF₃, CHF₂,OCF₃, OCHF₂, heteroaryl, or a straight chain, branched, or cyclic(C1-C8)-R⁸ wherein up to three CH₂ units may be replaced with O, CO, S,SO, SO₂, or NR⁷. In another embodiment, R⁴ is H, F, Cl, OH, CH₃, CHF₂,CF₃, OCH₃, OCHF₂, OCF₃, CO₂CH₃, CH₂OH, SO₂CH₃, CN, NHSO₂CH₃, C₂H₅,OC₂H₅, OCF₂CHFCl, OCH₂CF₃, O(CH₂)₂CH₃, OCH(CH₃)₂, O(CH₂)₂OH, OCH₂OCH₃,SCH₃, CON(CH₃)₂, NHCO₂tBu,

In another embodiment, R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH,OR⁷, NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷, CO₂R⁷, CON(R⁷)₂, SO₂N(R⁷)₂, CF₃, OCF₃,or a straight chain, branched, or cyclic (C1-C8)-R⁸ wherein up to threeCH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁷. In anotherembodiment, R⁵ is H, F, Cl, CH₃, C₂H₅, CH(CH₃)₂, tBu, OH, OCH₃, OC₂H₅,OCH(CH₃)₂, CH₂OH, CF₃, OCF₃, CN, CO₂CH₃, CONH₂, N(CH₃)SO₂CH₃, SO₂NH₂ orSO₂CH₃.

In another embodiment, R⁶ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6alkoxy, halo, CN, OH, OR⁷, SR⁷, SOR⁷, SO₂R⁷, NR⁷COR⁷, SO₂N(R⁷)₂,CON(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, heteroaryl or a straightchain, branched, or cyclic (C1-C8)-R⁸ wherein up to three CH₂ units maybe replaced with O, CO, S, SO, SO₂, or NR⁷. In another embodiment, R⁶ isH, F, Cl, CH₃, CF₃, OCH₃, OC₂H₅, CH₂CH₂OH, OCF₃, OCHF₂, SOCH(CH₃)₂,SO₂CH₃, SO₂CH(CH₃)₂, SO₂CHF₂, SO₂CF₃, SO₂C₂H₅, SO₂CH₂CH(CH₃)₂, SO₂tBu,OH, CN, CH₂CH₃, OCH₂CF₃, O(CH₂)₂OH, NHC(═O)CH₃, OCH₂C(═O)NH₂,

O(CH₂)₂CH₃,

O(CH₂)₃OH, O(CH₂)₂OCH₃,

O(CH₂)₂OCF₃,

O(CH₂)₂SO₂CH₃, tBu,

OtBu,

O(CH₂)₃OCH₃, O(CH₂)₂OC₂H₅,

O(CH₂)₂N(CH₃)₂,

OCH₂Ph, SO₂NHCH₃, SO₂N(CH₃)₂, SO₂NHCH₂CH₃, SO₂N(CH₃)CH(CH₃)₂,SO₂CH₂CH₂OH, CONHCH(CH₃)₂ or OCH₂CO₂H.

In another embodiment, two occurrences of R⁴ and R⁵ are both C1-C6 alkyland together with the carbons to which they are attached form anoptionally substituted ring comprising up to 2 heteroatoms. In anotherembodiment, two occurrences of R⁵ and R⁶ are C1-C6 alkyl and togetherwith the carbons to which they are attached form an optionallysubstituted ring comprising up to 2 heteroatoms.

In another embodiment, R⁴ is H. In another embodiment, R⁵ is halo, CF₃,C₁-C₆ alkyl, or C1-C6 alkoxy. In another embodiment, R⁵ is C1-C6 alkoxy.In another embodiment, R⁶ is C1-C6 alkyl or C1-C6 alkoxy. In anotherembodiment, R⁶ is C1-C6 alkyl.

In another embodiment, R⁴ is H; R⁵ is halo, CF₃, C1-C6 alkyl, or C1-C6alkoxy; and R⁶ is C1-C6 alkyl or C1-C6 alkoxy. In another embodiment, R⁴is H, R⁵ is C1-C6 alkoxy, and R⁶ is C1-C6 alkyl.

In another embodiment, R⁴ is H, and R⁵ and R⁶ are alkoxy. In anotherembodiment, R⁴ is halo, R⁵ is H, and R⁶ is alkoxy. In anotherembodiment, R⁴ and R⁵ are H, and R⁶ is SO₂R⁷. In another embodiment, R⁴and R⁵ are H, and R⁶ is SO₂NR⁷.

In another embodiment,

is selected from:

In another embodiment, the invention relates to a compound of formula Iand the attendant definitions, wherein A is heteroaryl or heterocyclic.In another embodiment, A is selected from:

In another embodiment, the invention relates to a compound of formula Iand the attendant definitions, wherein the compound has formula IA:

wherein:

-   R⁴ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH,    OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷,    CON(R⁷)₂, SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl,    heteroaryl or a straight chain, branched, or cyclic (C1-C8)-R⁸    wherein up to three CH₂ units may be replaced with O, CO, S, SO,    SO₂, or NR⁷;-   R⁵ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8    cycloalkoxy, halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷,    CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂, SO₂N(R)₂, CF₃, OCF₃, OCHF₂,    heterocycloalkyl, aryl, heteroaryl or a straight chain, branched, or    cyclic (C1-C8)-R⁸ wherein up to three CH₂ units may be replaced with    O, CO, S, SO, SO₂, or NR⁷;-   R⁶ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH,    OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SR⁷, SOR⁷, SO₂R⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷,    CON(R⁷)₂, SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl,    heteroaryl or a straight chain, branched, or cyclic (C1-C8)-R⁸    wherein up to three CH₂ units may be replaced with O, CO, S, SO,    SO₂, or NR⁷; or-   two occurrences of R⁴ and R⁵, or R⁵ and R⁶ are both C1-C6 alkyl and    together with the carbons to which they are attached form an    optionally substituted ring comprising up to 2 heteroatoms.

In another embodiment, the invention relates to a compound of formula IAand the attendant definitions, wherein R¹ is C1-C6 alkyl, C1-C6 alkoxy,halo, CN, CON(R⁷)₂, or (C1-C6)-R⁸ wherein up to two CH₂ units may bereplaced with O or NR⁷. In another embodiment, R¹ is F, Cl, CN, CH₃,CH₂OH, CH₂N(CH₃)₂, CH₂NH₂, CONHCH₃, CON(CH₃)₂, CH₂OCH₃.

In another embodiment, the invention relates to a compound of formula IAand the attendant definitions, wherein R² is C1-C6 alkyl, CN, CF₃,CON(R⁷)₂, SO₂R⁷, or (C1-C6)-R⁸ wherein up to two CH₂ units may bereplaced with O or NR⁷. In another embodiment, R² is CH₃, CF₃, CH₂OH,CN, SO₂CH₃, SOCH₃, CH₂NH₂, CH₂NHCOCH₃, CH₂NHCOH, COCH₃, or CONHCH₃.

In another embodiment, the invention relates to a compound of formula IAand the attendant definitions, wherein R³ is C1-C6 alkyl or 2occurrences of R³ taken together form a C3-C8 cycloalkyl group. Inanother embodiment. R³ is CH₃. In another embodiment, 2 occurrences ofR³ taken together form a C3-C8 cycloalkyl group.

In another embodiment, the invention relates to a compound of formula IAand the attendant definitions, wherein R⁴ is H, C1-C6 alkyl, C1-C6alkoxy, halo, CN, OH, OR⁷, CHF₂, CF₃, OCF₃, OCHF₂, SO₂R⁷, SOR⁷, SR⁷,NR⁷CO₂R⁷, heteroaryl, or a straight chain, branched, or cyclic(C1-C8)-R⁸ wherein up to three CH₂ units may be replaced with O, CO, S,SO, SO₂, or NR⁷. In another embodiment, R⁴ is H, F, Cl, OH, CH₃, CHF₂,CF₃, OCH₃, OCHF₂, OCF₃, CO₂CH₃, CH₂OH, SO₂CH₃, CN, NHCO₂tBu, C₂H₅,OCF₂CHFCl,

In another embodiment, the invention relates to a compound of formula IAand the attendant definitions, wherein R⁵ is H, C1-C6 alkyl, C1-C6alkoxy, halo, CN, OH, OR⁷, NR⁷SO₂R⁷, SO₂R⁷, SOR⁷, CO₂R⁷, CON(R⁷)₂,SO₂N(R⁷)₂, CF₃, OCF₃, or a straight chain, branched, or cyclic(C1-C8)-R⁸ wherein up to three CH₂ units may be replaced with O, CO, S,SO, SO₂, or NR⁷. In another embodiment, R⁵ is H, F, Cl, CH₃, C₂H₅, tBu,OH, OCH₃, OC₂H₅, OCH(CH₃)₂, CH₂OH, CF₃, OCF₃, CN, CO₂CH₃, CONH₂,N(CH₃)SO₂CH₃, SO₂NH₂ or SO₂CH₃.

In another embodiment, the invention relates to a compound of formula IAand the attendant definitions, wherein R⁶ is H, C1-C6 alkyl, C3-C8cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, SR⁷, SOR⁷, SO₂R⁷, NR⁷COR⁷,SO₂N(R⁷)₂, CF₃, OCF₃, heteroaryl, or a straight chain, branched, orcyclic (C1-C8)-R⁸, wherein up to three CH₂ units may be replaced with O,CO, S, SO, SO₂, or NR⁷. In another embodiment, R⁶ is H, F, CH₃, CF₃,OCH₃, OCF₃, SO₂CH₃, SO₂C₂H₅, SO₂CH(CH₃)₂, SO₂CH₂CH(CH₃)₂, SO₂tBu,SO₂CHF₂, CN, CH₂CH₃, tBu, CH₂CH₂OH, C(CH₃)₂OH, OCH₂CF₃, O(CH₂)₂OH,NHC(═O)CH₃, OCH₂C(═O)NH₂,

O(CH₂)₂CH₃,

O(CH₂)₃OH, O(CH₂)₂OCH₃,

O(CH₂)₂OCF₃,

O(CH₂)₂SO₂CH₃, tBu,

OtBu,

O(CH₂)₃OCH₃, O(CH₂)₂OC₂H₅,

O(CH₂)₂N(CH₃)₂,

OCH₂Ph, SO₂NHCH₃, SO₂NHCH₂CH₃, SO₂CH₂CH₂OH or OCH₂CO₂H.

In another embodiment, the invention relates to a compound of formula IAand the attendant definitions, wherein m is 0 or 1. In anotherembodiment, m is 0.

In another embodiment, the invention relates to a compound of formula IAand the attendant definitions, wherein n is 0, 1 or 2. In anotherembodiment, n is 0. In another embodiment, n is 1. In anotherembodiment, n is 2.

In another embodiment, the invention relates to a compound of formula IAand the attendant definitions, wherein o is 0, 1 or 2. In anotherembodiment, o is 0. In another embodiment, o is 1. In anotherembodiment, o is 2, and the two occurrences of R³ form a C3-C8cycloalkyl group.

In another embodiment, the invention relates to a compound of formula IAand the attendant definitions, wherein

is selected from:

In another embodiment, the invention relates to a compound of formula Iand the attendant definitions, wherein the compound has formula IB:

wherein:

-   R⁴ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH,    OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷,    CON(R⁷)₂, SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl,    heteroaryl or a straight chain, branched, or cyclic (C1-C8)-R⁸    wherein up to three CH₂ units may be replaced with O, CO, S, SO,    SO₂, or NR⁷;-   R⁵ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8    cycloalkoxy, halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷,    CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂, SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂,    heterocycloalkyl, aryl, heteroaryl or a straight chain, branched, or    cyclic (C1-C8)-R⁸ wherein up to three CH₂ units may be replaced with    O, CO, S, SO, SO₂, or NR⁷;-   R⁶ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH,    OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SOR⁷, SO₂R⁷, SR⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷,    CON(R⁷)₂, SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl,    heteroaryl or a straight chain, branched, or cyclic (C1-C8)-R⁸    wherein up to three CH₂ units may be replaced with O, CO, S, SO,    SO₂, or NR⁷; or-   two occurrences of R⁴ and R⁵, or R⁵ and R⁶ are both C1-C6 alkyl and    together with the carbons to which they are attached form an    optionally substituted ring comprising up to 2 heteroatoms.

In another embodiment, the invention relates to a compound of formula IBand the attendant definitions, wherein R¹ is halo or C1-C6 alkoxy. Inanother embodiment, R¹ is F, Cl or OCH₃.

In another embodiment, the invention relates to a compound of formula IBand the attendant definitions, wherein R² is C1-C6 alkyl, CF₃ or(C1-C6)-R⁸ wherein up to two CH₂ units may be replaced with O or NR⁷. Inanother embodiment, R² is CH₃, CF₃, C₂H₅, CH₂CF₃, or (CH₂)₂OCH₃.

In another embodiment, the invention relates to a compound of formula IBand the attendant definitions, wherein R⁴ is H, C1-C6 alkyl, C1-C6alkoxy, halo, CN, OH, OR⁷, CON(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, SOR⁷, CO₂R⁷,NR⁷CO₂R⁷, CHF₂, CF₃, OCF₃, OCHF₂, heteroaryl, or a straight chain,branched, or cyclic (C1-C8)-R⁸ wherein up to three CH₂ units may bereplaced with O, CO, S, SO, SO₂, or NR⁷. In another embodiment, R⁴ is H,F, Cl, OH, CH₃, CHF₂, CF₃, OCH₃, OCHF₂, OCF₃, SO₂CH₃, CN, NHSO₂CH₃,C₂H₅, OC₂H₅, OCF₂CHFCl, OCH₂CF₃, O(CH₂)₂CH₃, OCH₂OCH₃, OCH(CH₃)₂,O(CH₂)₂OH, SCH₃, CON(CH₃)₂, NHCO₂tBu.

In another embodiment, the invention relates to a compound of formula IBand the attendant definitions, wherein R⁵ is H, C1-C6 alkyl, C1-C6alkoxy, halo, CN, OH, OR⁷, CF₃, OCF₃, SO₂R⁷, SOR⁷, or a straight chain,branched, or cyclic (C1-C8)-R⁸ wherein up to three CH₂ units may bereplaced with O, CO, S, SO, SO₂, or NR⁷. In another embodiment, R⁵ is H,F, Cl, CH₃, CF₃, OCH₃, CH(CH₃)₂, OCH₂CH₃, CH₂OH, OCF₃, CN, SO₂CH₃ ortBu.

In another embodiment, R⁶ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH,OR⁷, CON(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, SOR⁷, CO₂R⁷, NR⁷CO₂R⁷, CHF₂, CF₃, OCF₃,OCHF₂, heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R⁸wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, orNR⁷. In another embodiment, the invention relates to a compound offormula IB and the attendant definitions, wherein R⁶ is H, F, Cl, OH,CH₃, CF₃, OCH₃, OCF₃, OCHF₂, SOCH(CH₃)₂, SO₂CH₃, SO₂CHF₂, SO₂CF₃,SO₂C₂H₅, SO₂CH(CH₃)₂, SO₂CH₂CH(CH₃)₂, SO₂tBu, SO₂NHCH₃, SO₂N(CH₃)₂,SO₂NHCH₂CH₃, SO₂N(CH₃)CH(CH₃)₂, CONHCH(CH₃)₂, CH₂CH₃, OCH₂CH₃,

O(CH₂)₂CH₃,

O(CH₂)₂OCH₃, O(CH₂)₂OCF₃, tBu,

OtBu,

or OCH₂Ph.

In another embodiment, the invention relates to a compound of formula IBand the attendant definitions, wherein two occurrences of R⁴ and R⁵ areboth C1-C6 alkyl and together with the carbons to which they areattached form an optionally substituted ring comprising up to 2heteroatoms. In another embodiment, two occurrences of R⁵ and R⁶ areboth C1-C6 alkyl and together with the carbons to which they areattached form an optionally substituted ring comprising up to 2heteroatoms.

In another embodiment, the invention relates to a compound of formula IBand the attendant definitions, wherein m is 0 or 1. In anotherembodiment, m is 0. In another embodiment, m is 1.

In another embodiment, the invention relates to a compound of formula IBand the attendant definitions, wherein n is 0, 1 or 2. In anotherembodiment, n is 1.

In another embodiment, the invention relates to a compound of formula IBand the attendant definitions, wherein o is 0.

In another embodiment, the invention relates to a compound of formula IBand the attendant definitions, wherein

is selected from:

In another embodiment, the invention relates to a compound selected fromTable 1:

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

77

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

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58

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60

61

62

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67

68

69

70

71

72

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98

99

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104

105

106

107

108

109

110

111

112

113

114

115

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511

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518

519

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In another aspect, the invention relates to a pharmaceutical compositioncomprising a compound of formula I and a pharmaceutically acceptablecarrier.

In another aspect, the invention relates to a method of inhibiting avoltage-gated sodium ion channel in:

(a) a patient; or

(b) a biological sample;

comprising administering to the patient, or contacting the biologicalsample, with a compound of formula I or a pharmaceutical compositioncomprising a compound of formula I. In another embodiment, thevoltage-gated sodium ion channel is NaV 1.7.

In another aspect, the invention relates to a method of treating orlessening the severity in a subject of acute, chronic, neuropathic, orinflammatory pain, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpatic neuralgia, general neuralgias, epilepsy or epilepsyconditions, neurodegenerative disorders, psychiatric disorders, anxiety,depression, dipolar disorder, myotonia, arrhythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, incontinence, visceral pain, osteoarthritis pain, postherpeticneuralgia, diabetic neuropathy, radicular pain, sciatica, back pain,head or neck pain, severe or intractable pain, nociceptive pain,breakthrough pain, postsurgical pain, cancer pain, stroke, cerebralischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-or exercise induced angina, palpitations, hypertension, migraine, orabormal gastro-intestinal motility, comprising administering aneffective amount of a compound of formula I or a pharmaceuticalcomposition comprising a compound of formula I.

In another embodiment, said method is used for treating or lessening theseverity of femur cancer pain; non-malignant chronic bone pain;rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lowback pain; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,abdominal pain; pancreatic; IBS pain; chronic and acute headache pain;migraine; tension headache, including, cluster headaches; chronic andacute neuropathic pain, post-herpatic neuralgia; diabetic neuropathy;HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Toothneuropathy; hereditary sensory neuropathies; peripheral nerve injury;painful neuromas; ectopic proximal and distal discharges; radiculopathy;chemotherapy induced neuropathic pain; radiotherapy-induced neuropathicpain; post-mastectomy pain; central pain; spinal cord injury pain;post-stroke pain; thalamic pain; complex regional pain syndrome; phantompain; intractable pain; acute pain, acute post-operative pain; acutemusculoskeletal pain; joint pain; mechanical low back pain; neck pain;tendonitis; injury/exercise pain; acute visceral pain, abdominal pain;pyelonephritis; appendicitis; cholecystitis; intestinal obstruction;hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acuteobstetric pain, labor pain; cesarean section pain; acute inflammatory,burn and trauma pain; acute intermittent pain, endometriosis; acuteherpes zoster pain; sickle cell anemia; acute pancreatitis; breakthroughpain; orofacial pain including sinusitis pain, dental pain; multiplesclerosis (MS) pain; pain in depression; leprosy pain; Behcet's diseasepain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painfullegs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry'sdisease pain; bladder and urogenital disease, including, urinaryincontinence; hyperactivity bladder; painful bladder syndrome;interstitial cyctitis (IC); prostatitis; complex regional pain syndrome(CRPS), type I and type II; widespread pain, paroxysmal extreme pain,pruritis, tinnitis, or angina-induced pain.

The compounds of the invention may be prepared readily using thefollowing methods. Illustrated below in Scheme 1 through Scheme 24 aremethods for preparing the compounds of the invention.

R is alkyl such as methyl.

PG=protective group such as BOC, benzyl, CBZ.H⁺: protic acid such as trifluoroacetic acid, para-toluene sulfonicacid, propionic acid, or dichloroacetic acid.

PG=protective group such as BOC, benzyl, CBZ.H⁺: protic acid such as trifluoroacetic acid, para-toluene sulfonicacid, propionic acid, or dichloroacetic acid.

R=benzyl, CO₂Bn, BOC, COCH₃, COCF₃, COAryl.

R=benzyl, BOC, COCH₃, COCF₃, COAryl.

X═Cl, Br, I, OTf; M=B(OR)₂, ZnCl, MgBr.

R₅=benzyl, CO₂Bn, BOC, COCH₃, COCF₃, COAryl.

R₅=benzyl, CO₂Bn, BOC, COCH₃, COCF₃, COAryl.

R₅═BOC, benzyl, CO₂Bn, COCH₃, COCF₃, COAryl.

R₅=benzyl, CO₂Bn, COCH₃, COCF₃, COAryl.

R₅═BOC, benzyl, CO₂Bn, COCH₃, COCF₃, COAryl; R⁶=alkyl.

R=benzyl, CO₂Bn, BOC, COCH₃, COCF₃, or COAryl.

R₅═BOC, benzyl, CO₂Bn, COCH₃, COCF₃, COAryl; R⁶═H, alkyl; X═Br, Cl.

R₅═BOC, benzyl, CO₂Bn, COCH₃, COCF₃, COAryl; R⁶=alkyl, aryl.

Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

As discussed above, the invention provides compounds that are inhibitorsof voltage-gated sodium ion channels, and thus the present compounds areuseful for the treatment of diseases, disorders, and conditionsincluding, but not limited to acute, chronic, neuropathic, orinflammatory pain, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsyconditions, neurodegenerative disorders, psychiatric disorders such asanxiety and depression, myotonia, arrhythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, and incontinence. Accordingly, in another aspect of theinvention, pharmaceutically acceptable compositions are provided,wherein these compositions comprise any of the compounds as describedherein, and optionally comprise a pharmaceutically acceptable carrier,adjuvant or vehicle. In certain embodiments, these compositionsoptionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of inventioncan exist in free form for treatment, or where appropriate, as apharmaceutically acceptable derivative thereof. According to theinvention, a pharmaceutically acceptable derivative includes, but is notlimited to, pharmaceutically acceptable salts, esters, salts of suchesters, or any other adduct or derivative which upon administration to asubject in need is capable of providing, directly or indirectly, acompound as otherwise described herein, or a metabolite or residuethereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a voltage-gated sodium ion channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of theinvention additionally comprise a pharmaceutically acceptable carrier,adjuvant, or vehicle, which, as used herein, includes any and allsolvents, diluents, or other liquid vehicle, dispersion or suspensionaids, surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. Remington's PharmaceuticalSciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton,Pa., 1980) discloses various carriers used in formulatingpharmaceutically acceptable compositions and known techniques for thepreparation thereof. Except insofar as any conventional carrier mediumis incompatible with the compounds of the invention, such as byproducing any undesirable biological effect or otherwise interacting ina deleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof this invention. Some examples of materials which can serve aspharmaceutically acceptable carriers include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, serum proteins,such as human serum albumin, buffer substances such as phosphates,glycine, sorbic acid, or potassium sorbate, partial glyceride mixturesof saturated vegetable fatty acids, water, salts or electrolytes, suchas protamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, dipolar disorder, myotonia, arrhythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, incontinence, visceral pain, osteoarthritis pain, postherpeticneuralgia, diabetic neuropathy, radicular pain, sciatica, back pain,head or neck pain, severe or intractable pain, nociceptive pain,breakthrough pain, postsurgical pain, or cancer pain is providedcomprising administering an effective amount of a compound, or apharmaceutically acceptable composition comprising a compound to asubject in need thereof.

In certain embodiments, a method of treatment or lessening the severityof stroke, cerebral ischemia, traumatic brain injury, amyotrophiclateral sclerosis, stress- or exercise induced angina, palpitations,hypertension, migraine, or abormal gastro-intestinal motility isprovided comprising administering an effective amount of a compound, ora pharmaceutically acceptable composition comprising a compound to asubject in need thereof.

In certain embodiments, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain isprovided comprising administering an effective amount of a compound or apharmaceutically acceptable composition to a subject in need thereof. Incertain other embodiments, a method for the treatment or lessening theseverity of radicular pain, sciatica, back pain, head pain, or neck painis provided comprising administering an effective amount of a compoundor a pharmaceutically acceptable composition to a subject in needthereof. In still other embodiments, a method for the treatment orlessening the severity of severe or intractable pain, acute pain,postsurgical pain, back pain, tinnitis or cancer pain is providedcomprising administering an effective amount of a compound or apharmaceutically acceptable composition to a subject in need thereof.

In certain embodiments, a method for the treatment or lessening theseverity of femur cancer pain; non-malignant chronic bone pain;rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lowback pain; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,including, abdominal; pancreatic; IBS pain; chronic and acute headachepain; migraine; tension headache, including, cluster headaches; chronicand acute neuropathic pain, including, post-herpetic neuralgia; diabeticneuropathy; HIV-associated neuropathy; trigeminal neuralgia;Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies;peripheral nerve injury; painful neuromas; ectopic proximal and distaldischarges; radiculopathy; chemotherapy induced neuropathic pain;radiotherapy-induced neuropathic pain; post-mastectomy pain; centralpain; spinal cord injury pain; post-stroke pain; thalamic pain; complexregional pain syndrome; phantom pain; intractable pain; acute pain,acute post-operative pain; acute musculoskeletal pain; joint pain;mechanical low back pain; neck pain; tendonitis; injury/exercise pain;acute visceral pain, including, abdominal pain; pyelonephritis;appendicitis; cholecystitis; intestinal obstruction; hernias; etc; chestpain, including, cardiac Pain; pelvic pain, renal colic pain, acuteobstetric pain, including, labor pain; cesarean section pain; acuteinflammatory, burn and trauma pain; acute intermittent pain, including,endometriosis; acute herpes zoster pain; sickle cell anemia; acutepancreatitis; breakthrough pain; orofacial pain including sinusitispain, dental pain; multiple sclerosis (MS) pain; pain in depression;leprosy pain; behcet's disease pain; adiposis dolorosa; phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome;erythromelalgia pain; Fabry's disease pain; bladder and urogenitaldisease, including, urinary incontinence; hyperactivity bladder; painfulbladder syndrome; interstitial cyctitis (IC); or prostatitis; complexregional pain syndrome (CRPS), type I and type II; angina-induced painis provided, comprising administering an effective amount of a compoundor a pharmaceutically acceptable composition to a subject in needthereof.

In certain embodiments of the invention an “effective amount” of thecompound or pharmaceutically acceptable composition is that amounteffective for treating or lessening the severity of one or more ofacute, chronic, neuropathic, or inflammatory pain, arthritis, migraine,cluster headaches, trigeminal neuralgia, herpetic neuralgia, generalneuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrhythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, tinnitis or cancer pain.

The compounds and compositions, according to the method of theinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of acute, chronic, neuropathic, or inflammatory pain, arthritis,migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia,general neuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrhythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, tinnitis or cancer pain. The exact amount requiredwill vary from subject to subject, depending on the species, age, andgeneral condition of the subject, the severity of the infection, theparticular agent, its mode of administration, and the like. Thecompounds of the invention are preferably formulated in dosage unit formfor ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the subject to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the invention will be decided by the attending physicianwithin the scope of sound medical judgment. The specific effective doselevel for any particular subject or organism will depend upon a varietyof factors including the disorder being treated and the severity of thedisorder; the activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the subject; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed, and like factors well known in the medical arts. Theterm “subject” or “patient”, as used herein, means an animal, preferablya mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the invention, it isoften desirable to slow the absorption of the compound from subcutaneousor intramuscular injection. This may be accomplished by the use of aliquid suspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar—agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms are prepared by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium ion channels. In one embodiment,the compounds and compositions of the invention are inhibitors of one ormore of NaV1.1, NaV 1.2, NaV 1.3, NaV 1.4, NaV 1.5, NaV 1.6, NaV1.7, NaV1.8, or NaV 1.9, and thus, without wishing to be bound by any particulartheory, the compounds and compositions are particularly useful fortreating or lessening the severity of a disease, condition, or disorderwhere activation or hyperactivity of one or more of NaV1.1, NaV1.2,NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9 is implicatedin the disease, condition, or disorder. When activation or hyperactivityof NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, orNaV1.9 is implicated in a particular disease, condition, or disorder,the disease, condition, or disorder may also be referred to as a“NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 orNaV1.9-mediated disease, condition or disorder”. Accordingly, in anotheraspect, the invention provides a method for treating or lessening theseverity of a disease, condition, or disorder where activation orhyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5,NaV1.6, NaV1.7, NaV1.8, or NaV1.9 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor ofNaV 1.1, NaV 1.2, NaV 1.3, NaV 1.4, NaV1.5, NaV1.6, NaV 1.7, NaV1.8, orNaV1.9 may be assayed according to methods described generally in theExamples herein, or according to methods available to one of ordinaryskill in the art.

In certain exemplary embodiments, compounds of the invention are usefulas inhibitors of NaV1.7 and/or NaV1.8.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the invention can be employed in combinationtherapies, that is, the compounds and pharmaceutically acceptablecompositions can be administered concurrently with, prior to, orsubsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”. For example, exemplary additional therapeutic agentsinclude, but are not limited to: nonopioid analgesics (indoles such asEtodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such saNabumetone; oxicams such as Piroxicam; para-aminophenol derivatives,such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen,Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylatessuch as Asprin, Choline magnesium trisalicylate, Diflunisal; fenamatessuch as meclofenamic acid, Mefenamic acid; and pyrazoles such asPhenylbutazone); or opioid (narcotic) agonists (such as Codeine,Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine,Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol,Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesicapproaches may be utilized in conjunction with administration of one ormore compounds of the invention. For example, anesthesiologic(intraspinal infusion, neural blocade), neurosurgical (neurolysis of CNSpathways), neurostimulatory (transcutaneous electrical nervestimulation, dorsal column stimulation), physiatric (physical therapy,orthotic devices, diathermy), or psychologic (cognitivemethods-hypnosis, biofeedback, or behavioral methods) approaches mayalso be utilized. Additional appropriate therapeutic agents orapproaches are described generally in The Merck Manual, SeventeenthEdition, Ed. Mark H. Beers and Robert Berkow, Merck ResearchLaboratories, 1999, and the Food and Drug Administration website,www.fda.gov, the entire contents of which are hereby incorporated byreference.

In another embodiment, additional appropriate therapeutic agents areselected from the following:

(1) an opioid analgesic, e.g. morphine, heroin, hydromorphone,oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl,cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene,nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol,nalbuphine or pentazocine;

(2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal,flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen,nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone,piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

(3) a barbiturate sedative, e.g. amobarbital, aprobarbital,butabarbital, butabital, mephobarbital, metharbital, methohexital,pentobarbital, phenobartital, secobarbital, talbutal, theamylal orthiopental;

(4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide,clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam ortriazolam;

(5) an H₁ antagonist having a sedative action, e.g. diphenhydramine,pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

(6) a sedative such as glutethimide, meprobamate, methaqualone ordichloralphenazone;

(7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol,chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;

(8) an NMDA receptor antagonist, e.g. dextromethorphan((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinolinequinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine,EN-3231 (MorphiDex(R), a combination formulation of morphine anddextromethorphan), topiramate, neramexane or perzinfotel including anNR2B antagonist, e.g. ifenprodil, traxoprodil or(−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;

(9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine,guanfacine, dexmetatomidine, modafinil, or4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline;

(10) a tricyclic antidepressant, e.g. desipramine, imipramine,amitriptyline or nortriptyline;

(11) an anticonvulsant, e.g. carbamazepine, lamotrigine, topiratmate orvalproate;

(12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1antagonist, e.g.([alpha]R,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione(TAK-637),5-[R2R,3S)-2-[(1R)-[43,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one(MK-869), aprepitant, lanepitant, dapitant or3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine(2S,3S);

(13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine,tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

(14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib,valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

(15) a coal-tar analgesic, in particular paracetamol;

(16) a neuroleptic such as droperidol, chlorpromazine, haloperidol,perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine,clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole,aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone,raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride,balaperidone, palindore, eplivanserin, osanetant, rimonabant,meclinertant, Miraxion(R) or sarizotan;

(17) a vanilloid receptor agonist (e.g. resinferatoxin) or antagonist(e.g. capsazepine);

(18) a beta-adrenergic such as propranolol;

(19) a local anaesthetic such as mexiletine;

(20) a corticosteroid such as dexamethasone;

(21) a 5-HT receptor agonist or antagonist, particularly a 5-HTi B/I Dagonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan orrizatriptan;

(22) a 5-HT2A receptor antagonist such asR(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol(MDL-100907);

(23) a cholinergic (nicotinic) analgesic, such as ispronicline(TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403),(R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

(24) Tramadol(R);

(25) a PDEV inhibitor, such as5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(sildenafil),(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]-pyrido[3,4-b]indole-1,4-dione(IC-351 or tadalafil),2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one(vardenafil),5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-<i]pyrimidin-7-one,5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-<i]pyrimidm-7-one,5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;(z) an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin,(l[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-aceticacid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid,(3S,5R)-3-amino-5-methyl-heptanoic acid,(3S,5R)-3-amino-5-methyl-octanoic acid,(2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline,[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,(3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,(3S,5R)-3-aminomethyl-5-methyl-octanoic acid,(3S,5R)-3-amino-5-methyl-nonanoic acid,(3S,5R)-3-amino-5-methyl-octanoic acid,(3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and(3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;

(26) a cannabinoid;

(27) metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;

(28) a serotonin reuptake inhibitor such as sertraline, sertralinemetabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetinedesmethyl metabolite), fluvoxamine, paroxetine, citalopram, citaloprammetabolite desmethylcitalopram, escitalopram, d,l-fenfluramine,femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine,nefazodone, cericlamine and trazodone;

(29) a noradrenaline (norepinephrine) reuptake inhibitor, such asmaprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,tomoxetine, mianserin, buproprion, buproprion metabolitehydroxybuproprion, nomifensine and viloxazine (Vivalan(R)), especially aselective noradrenaline reuptake inhibitor such as reboxetine, inparticular (S,S)-reboxetine;

(30) a dual serotonin-noradrenaline reuptake inhibitor, such asvenlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine,milnacipran and imipramine;

(31) an inducible nitric oxide synthase (iNOS) inhibitor such asS-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thioJ-S-chloro-5-pyridinecarbonitrile;2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile,(2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3pyridinecarbonitrile,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, orguanidinoethyldisulfide;

(32) an acetylcholinesterase inhibitor such as donepezil;

(33) a prostaglandin E2 subtype 4 (EP4) antagonist such as7V-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl)amino)-carbonyl]-4-methylbenzenesulfonamideor4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoicacid;

(34) a leukotriene B4 antagonist; such as1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylicacid (CP-105696),5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valericacid (ONO-4057) or DPC-11870,

(35) a 5-lipoxygenase inhibitor, such as zileuton,6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy-methyl]-1-methyl-2-quinolone(ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl),1,4-benzoquinone(CV-6504); (36) a sodium channel blocker, such as lidocaine;

(36) a 5-HT3 antagonist, such as ondansetron; and the pharmaceuticallyacceptable salts and solvates thereof.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, theinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the invention as describedgenerally above, and in classes and subclasses herein, and a carriersuitable for coating said implantable device. In still another aspect,the invention includes an implantable device coated with a compositioncomprising a compound of the invention as described generally above, andin classes and subclasses herein, and a carrier suitable for coatingsaid implantable device. Suitable coatings and the general preparationof coated implantable devices are described in U.S. Pat. Nos. 6,099,562;5,886,026; and 5,304,121. The coatings are typically biocompatiblepolymeric materials such as a hydrogel polymer, polymethyldisiloxane,polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinylacetate, and mixtures thereof. The coatings may optionally be furthercovered by a suitable topcoat of fluorosilicone, polysaccarides,polyethylene glycol, phospholipids or combinations thereof to impartcontrolled release characteristics in the composition.

Another aspect of the invention relates to inhibiting one or more ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, orNaV1.9, activity in a biological sample or a subject, which methodcomprises administering to the subject, or contacting said biologicalsample with a compound of formula I or a composition comprising saidcompound. The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of one or more of NaV 1.1, NaV 1.2, NaV 1.3, NaV 1.4, NaV1.5,NaV1.6, NaV1.7, NaV1.8, or NaV1.9, activity in a biological sample isuseful for a variety of purposes that are known to one of skill in theart. Examples of such purposes include, but are not limited to, thestudy of sodium ion channels in biological and pathological phenomena;and the comparative evaluation of new sodium ion channel inhibitors.

EXAMPLES General Methods

¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were obtained assolutions in deuterioacetonitrile (CD₃CN), chloroform-d (CDCl₃) ordimethyl sulfoxide-D₆ (DMSO). Mass spectra (MS) were obtained using anApplied Biosystems API EX LC/MS system equipped with a Phenomenex50×4.60 mm luna-5μ C18 column. The LC/MS eluting system was 1-99% or10-99% acetonitrile in H₂O with 0.035% v/v trifluoroacetic acid, 0.035%v/v formic acid, 5 mM HCl or 5 mM ammonium formate using a 3 or 15minute linear gradient and a flow rate of 12 mL/minute. Silica gelchromatography was performed using silica gel-60 with a particle size of230-400 mesh. Pyridine, dichloromethane (CH₂Cl₂), tetrahydrofuran (THF),dimethylformamide (DMF), acetonitrile (ACN), methanol (MeOH), and1,4-dioxane were from Aldrich Sure-Seal bottles kept under dry nitrogen.All reactions were stirred magnetically unless otherwise noted.

Spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]hydrochloridesalt Step 1: 2-(1H-Pyrrol-1-yl)phenol

A 5 L 3-neck round bottom flask was fitted with a mechanical stirrer, aheating mantle, a water cooled reflux condenser, a temperatureprobe/controller and a nitrogen inlet/outlet. The vessel was chargedwith (50 g, 0.46 mol) of 2-aminophenol and acetic acid (750 mL) whichprovided a very dark solution. Stirring was commenced and the vessel wascharged with 2,5-dimethoxytetrahydrofuran (59.4 mL, 0.458 mol) dropwiseover 2 minutes. The dark mixture was then heated at 100° C. for 15 min.The mixture was allowed to cool to room temperature and was filteredthrough a pad of Celite to remove residual solids. The filtrate wasconcentrated under reduced pressure azeotroping with toluene. Theresidual oil was dissolved in ethyl acetate (1000 mL) and waspartitioned with water (500 mL). The organic layer was separated and waswashed with water (500 mL), dried over sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure to provide2-(1H-pyrrol-1-yl)phenol (54 g, 74%) as a dark oil. ESI-MS m/z calc.159.1. found 160.2 (M+1)⁺. Retention time: 2.67 minutes (3 min run). ¹HNMR (400 MHz, CDCl₃) δ 7.37-7.23 (m, 2H), 7.13-6.97 (m, 2H), 6.91 (t,J=1.9 Hz, 2H), 6.43 (t, J=1.9 Hz, 2H), 5.35 (s, 1H).3-(1H-Pyrrol-1-yl)pyridin-2-ol was also synthesized using the proceduredescribed above.

Step 2: tert-Butylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine-1-1′-carboxylate

A 5 L 3-neck round bottom flask was fitted with a mechanical stirrer, anaddition funnel, a temperature probe/controller and a nitrogeninlet/outlet. The vessel was charged under nitrogen with2-(1H-pyrrol-1-yl)phenol (40 g, 0.25 mol) and dichloromethane (800 mL).Stirring was commenced and the dark solution was charged with tert-butyl4-oxopiperidine-1-carboxylate (55.1 g, 0.276 mol) added as a solid inone portion. An addition funnel was charged with TFA (38.7 ml, 0.503mol) which was subsequently added dropwise over 15 minutes. The darkmixture was continued to stir at ambient temperature for 5 hours atwhich point the contents of the reaction vessel were transferred to aseparatory funnel and were partitioned with water (500 mL). The organiclayer was separated and was washed with 1M NaOH (2×250 mL), dried oversodium sulfate and filtered. The filtrate was concentrated under reducedpressure to provide a clear amber oil (105 g). The material was purifiedby silica gel column flash chromatography (4:1 Hex/EtOAc, 250 mLfractions) to provide (51 g, 60%) of tert-butylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylateas a clear amber oil. ESI-MS m/z calc. 340.2. found 341.3 (M+1)⁺.Retention time: 2.17 minutes (3 min run). ¹H NMR (400 MHz, CDCl₃) δ 7.35(d, J=7.5 Hz, 1H), 7.19-7.13 (m, 1H), 7.10-7.01 (m, 3H), 6.34 (t, J=3.1Hz, 1H), 6.03 (d, J=3.4 Hz, 1H), 4.02 (s, 2H), 3.30 (s, 2H), 2.14-1.99(m, 2H), 1.90 (td, J=13.3, 4.9 Hz, 2H), 1.48 (s, 9H).

Step 3:Spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]hydrochloridesalt

A 5 L 3-neck round bottom flask was fitted with a mechanical stirrer, anaddition funnel, a temperature probe/controller and a nitrogeninlet/outlet. The vessel was charged under nitrogen with a clear ambersolution of tert-butylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylateand(50 g, 0.15 mol) and toluene (250 mL). Stirring was commenced and theaddition funnel was charged with (73 mL, 0.29 mol) of 4M HCl in1,4-dioxane which was added dropwise over 10 minutes resulting in a verydark solution. The mixture was continued to stir at ambient temperaturefor 1 h before the reaction mixture was filtered to remove the residualsolids. The filtrate was concentrated under reduced pressure to providea solid which was triturated with diethyl ether (2×200 mL) and was thendried under vacuum to provide (31 g, 76%) ofspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]hydrochlorideas an off-white solid. ESI-MS m/z calc. 240.1. found 241.3 (M+1)⁺.Retention time: 1.21 minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 9.45(s, 2H), 7.76-7.62 (m, 1H), 7.55 (dd, J=2.8, 1.3 Hz, 1H), 7.23-7.08 (m,3H), 6.31 (t, J=3.2 Hz, 1H), 6.11 (dd, J=3.4, 1.3 Hz, 1H), 3.29-3.13 (m,4H), 2.25 (td, J=14.4, 5.0 Hz, 2H), 2.09 (d, J=14.1 Hz, 2H).

The following compounds were prepared using the procedures describedabove:7-Fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]hydrochloride:ESI-MS m/z calc. 258.1 (—HCl). found 259.2 (M+1)⁺. Retention time: 1.29minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 9.52 (s, 2H), 7.76 (dd,J=8.9, 5.6 Hz, 1H), 7.58-7.54 (m, 1H), 7.20 (dd, J=9.6, 2.8 Hz, 1H),6.97 (td, J=8.7, 2.8 Hz, 1H), 6.31 (t, J=3.2 Hz, 1H), 6.11 (dd, J=3.4,1.2 Hz, 1H), 3.30-3.14 (m, 4H), 2.28 (td, J=14.7, 5.5 Hz, 2H), 2.11 (d,J=14.1 Hz, 2H) and7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]hydrochloride:ESI-MS m/z calc. 274.1 (—HCl). found 275.2 (M+1)⁺. Retention time: 1.38minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 9.38 (s, 2H), 7.75 (d,J=8.6 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.39 (d, J=2.2 Hz, 1H), 7.17 (dd,J=8.6, 2.2 Hz, 1H), 6.33 (t, J=3.2 Hz, 1H), 6.13 (d, J=3.0 Hz, 1H),3.30-3.11 (m, 4H), 2.32-2.17 (m, 2H), 2.10 (d, J=14.1 Hz, 2H).

Spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carbonitrileStep 1: 1′-tert-Butyl 7-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′,7-dicarboxylate

Trifluoroacetic acid (3.15 g, 2.13 mL, 27.6 mmol) was added dropwise toa solution of methyl 3-hydroxy-4-pyrrol-1-yl-benzoate (3.00 g, 13.8mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (3.00 g, 15.2 mmol)in dichloromethane (60 mL) and the reaction mixture was stirred at roomtemperature for 6 hours. The reaction mixture was washed with water and1N NaOH. The organics were dried over sodium sulfate, filtered andevaporated. The residue was purified by silica gel chromatographyeluting with 0-30% EtOAc in Hexanes. The pure fractions were combinedand concentrated to give 1′-tert-butyl 7-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′,7-dicarboxylate.ESI-MS m/z calc. 398.4. found 399.5 (M+1)⁺. Retention time: 2.13 minutes(3 min run).

Step 2:1′-(tert-Butoxycarbonyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylicacid

A solution of 1′-ten-butyl 7-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′,7-dicarboxylate(3.5 g, 8.8 mmol) in LiOH (18 mL of 2.0 M, 35.1 mmol) and dioxane (18mL) was stirred at 55° C. for 1 hour. The reaction mixture was dilutedwith ethyl acetate and was washed with water. The aqueous layer wasacidified with 1N HCl and the product was extracted into ethyl acetate.The organics were dried over sodium sulfate, filtered and evaporated toyield1′-(tert-butoxycarbonyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylicacid which was used without further purification. ESI-MS m/z calc.384.4. found 385.3 (M+1)⁺. Retention time: 1.81 minutes (3 min run).

Step 3: tert-Butyl7-carbamoylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate

A solution of NH₄Cl (1.4 mL, 40 mmol) and Et₃N (5.6 mL, 40 mmol) in DMF(6 mL) was added to a solution of1-tert-butoxycarbonylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-carboxylicacid (3.1 g, 8.0 mmol), HATU (3.3 g, 8.8 mmol), and Et₃N (2.5 mL, 18mmol) in DMF (6 mL). The mixture was stirred at room temperature for 1h. The reaction mixture was diluted with ethyl acetate and was washedwith saturated sodium bicarbonate solution. The organics were dried oversodium sulfate, filtered and evaporated. Purification of the residue bysilica gel chromatography eluting with 0-100% EtOAc in Hexanes gavetert-butyl7′-carbamoylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(2.7 g, 89%). ESI-MS m/z calc. 383.4. found 384.7 (M+1)⁺. Retentiontime: 1.60 minutes (3 min run).

Step 4: tert-Butyl7-cyanospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate

A solution of tert-butyl7′-carbamoylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(2.7 g, 7.1 mmol) and cyanuric chloride (1.3 g, 7.1 mmol) in DMF (10 mL)was stirred at room temperature for 1 hour. The reaction was poured intowater and the product was extracted into ethyl acetate. The organicswere dried over sodium sulfate, filtered and evaporated to yield a crudemixture that was purified by silica gel chromatography eluting with0-100% EtOAc in Hexanes. Pure fractions were combined and concentratedto yield tert-butyl7-cyanospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate(1.1 g, 44%). ESI-MS m/z calc. 365.4. found 366.3 (M+1)⁺. Retentiontime: 2.00 minutes (3 min run).

Step 5:Spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carbonitrile

A solution of tert-butyl7′-cyanospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(1.1 g, 3.1 mmol) in HCl in dioxane (3.1 mL of 4.0 M, 12 mmol) wasstirred at room temperature for 1 hour. The reaction mixture wasevaporated to dryness to yieldspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carbonitrile(880 mg, 94%). ESI-MS m/z calc. 265.3. found 266.1 (M+1)⁺. Retentiontime: 0.92 minutes (3 min run).

Methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylatehydrochloride

A solution of 1′-tert-butyl 7-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′,7-dicarboxylate(1.8 g, 4.5 mmol) in HCl (4.5 mL, 4.0M in dioxanes, 18 mmol) was stirredat room temperature for 2 hours. The reaction mixture was evaporated todryness to give methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylatehydrochloride (1.5 g, quant). ESI-MS m/z calc. 298.3. found 299.5(M+1)⁺. Retention time: 1.06 minutes (3 min run).

1-Methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] Step1: 1′-Benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]

To a 0° C. solution ofspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (HCl salt) (1.0 g,3.6 mmol) in dry acetonitrile (10 mL), under nitrogen, was added NaHCO₃(1.5 g, 18 mmol) followed by dropwise addition of benzyl bromide (560μL, 4.7 mmol). The cooling bath was removed. Water (25 ml) was thenadded, and the organic solvent was removed under vacuum. The product wasextracted from the aqueous solution with EtOAc (3×150 mL). The organicphases were combined, washed with brine, dried with sodium sulfate,filtered, and concentrated under reduced pressure. The product waspurified by column chromatography (silica gel: 5-70% EtOAc in hexanes)to giver-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]660 mg,55%). ESI-MS m/z calc. 330.4. found 331.5 (M+1)⁺; Retention time: 1.23minutes (3 min run).

Step 2:1′-Benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde

N,N-Dimethylformamide (723 μL, 9.40 mmol), under nitrogen, was cooled to0° C. and POCl₃ (876 μL, 9.40 mmol) was added dropwise. The reaction wasstirred for 20 min at 0° C. and a white solid formed. A solution of1-benzylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (2.07 g,6.27 mmol) in dry DMF (15.5 mL) was added dropwise and the cooling bathwas removed. The reaction mixture was stirred for 2 h at 50° C., thencooled down to room temperature and poured onto ice. Sodium hydroxide (1M) was added until the pH reached 10, then the solution was acidified topH 6 with 3 M HCl. The mixture was then extracted with EtOAc. Theorganics were dried over sodium sulfate, filtered and concentrated. Theresidue was purified by column chromatography (silica gel: 10-70% EtOAcin hexanes) to give1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde(1.94 g, 86%). ESI-MS m/z calc. 358.4. found 359.3 (M+1)⁺; Retentiontime: 1.16 minutes (3 min run). ¹H NMR (400 MHz, CDCl₃) δ 9.66 (s, 1H),8.17-8.07 (m, 1H), 7.38-7.30 (m, 4H), 7.29-7.24 (m, 1H), 7.20-7.13 (m,2H), 7.09 (m, 2H), 6.20 (d, J=4.1 Hz, 1H), 3.59 (s, 2H), 2.76 (m, 2H),2.58-2.45 (m, 2H), 2.10-1.96 (m, 4H).

Step 3:(1′-Benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methanol

A solution of1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde(1.94 g, 5.40 mmol) in methanol (40 mL) was cooled to 0° C. Sodiumborohydride (409 mg, 10.8 mmol) was added in one portion and the coolingbath was removed. After stirring for 1 h at room temperature, thereaction was diluted with saturated aqueous NaHCO₃ (50 mL) and DCM (150mL). The organic layer was separated and the aqueous layer was extractedtwice more with DCM (150 mL). The organic layers were combined, dried,filtered and concentrated to give(1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methanol(1.66 g) as a white solid. The crude material was used in the next stepwithout purification.

Step 4:(1′-Benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methylacetate

A solution of(r-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methanol(1.66 g, 4.60 mmol) and 4-(dimethylamino)pyridine (561 mg, 4.60 mmol) indry THF (40 mL) was cooled to 0° C. Triethylamine (2.56 mL, 18.4 mmol)was then added to the reaction mixture followed by dropwise addition ofacetic anhydride (1.27 mL, 13.5 mmol). The reaction mixture was allowedto warm to room temperature and was stirred overnight. It was thenconcentrated and purified by column chromatography (silica gel: 10-40%EtOAc in hexanes) to give(1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methylacetate (1.32 g, 61% yield over two steps). ESI-MS m/z calc. 402.5.found 403.7 (M+1)⁺; Retention time: 1.31 minutes (3 min run).

Step 5:1-Methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]

To a solution of(1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methylacetate (300 mg, 0.75 mmol) in ethyl acetate (30 mL) was added aceticacid (17 μL, 0.30 mmol). The reaction was flushed with nitrogen then 10%Pd/C (40 mg, 0.37 mmol) was added. The reaction was placed underhydrogen gas and was stirred for 20 h at room temperature. Thesuspension was filtered through celite, concentrated, then purified bycolumn chromatography (silica gel: 0.1-15% methanol in dichloromethane)to give1-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (65mg, 34%). ESI-MS m/z calc. 254.3. found 255.3 (M+1)⁺; Retention time:1.93 minutes (3 min run). NMR (400 MHz, CDCl₃) δ 7.56 (d, J=7.9 Hz, 1H),7.16-6.99 (m, 3H), 6.03 (d, J=3.2 Hz, 1H), 5.94 (d, J=3.4 Hz, 1H), 3.14(t, J=12.2 Hz, 2H), 2.94 (d, J=12.3 Hz, 2H), 2.56 (s, 3H), 2.19 (m, 1H),2.04 (d, J=12.7 Hz, 2H), 1.97-1.84 (m, 2H).

1-(Trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]Step 1: tert-Butyl1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate

tert-Butylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (100mg, 0.29 mmol), trifluoromethanesulfonate5-(trifluoromethyl)dibenzothiophen-5-ium (300 mg, 0.73 mmol) and K₂CO₃(110 mg, 0.76 mmol) were combined in N,N-dimethylformamide (1 mL). Thereaction mixture was heated at 80° C. for 16 hours. The reaction mixturewas filtered and then purified by reverse phase HPLC 10-99% methanol inwater to give tert-butyl1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate(57 mg, 48%). ¹H NMR (400 MHz, CDCl₃) δ 7.66 (d, J=8.1 Hz, 1H),7.22-7.03 (m, 3H), 6.79 (d, J=3.9 Hz, 1H), 6.03 (d, J=3.9 Hz, 1H),4.27-3.75 (m, 2H), 3.39-3.10 (m, 2H), 2.13-1.96 (m, 2H), 1.95-1.78 (m,2H), 1.48 (s, 9H). ESI-MS m/z calc. 408.4. found 409.5 (M+1)⁺; Retentiontime: 2.38 minutes (3 min run).

Step 2:1-(Trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]hydrochloricacid

tert-Butyl1′-(trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(30 mg, 0.074 mmol) was dissolved in hydrogen chloride in dioxane (700μL of 4.0 M, 2.8 mmol). The reaction mixture was allowed to stand for 20minutes. The solvent was evaporated to give1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]hydrochloridewas then used without further purification (25 mg, 99%). ¹H NMR (400MHz, DMSO) δ 9.23 (br s, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.40-7.19 (m, 3H),7.05 (d, J=3.9 Hz, 1H), 6.38 (d, J=4.0 Hz, 1H), 3.42-3.04 (m, 4H),2.37-2.00 (m, 4H). ESI-MS m/z calc. 308.3. found 309.5 (M+1)⁺; Retentiontime: 1.53 minutes (3 min run).

1-(Trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]sulfate

To spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (5.20 g, 21.6mmol) in DMSO (104 mL) was added H₂SO₄ (1.27 mL, 23.8 mmol)(note:exothermic), ferrous sulfate heptahydrate (6.5 mL of 1.0 M, 6.5 mmol)followed by CF₃I (4.24 g, 21.6 mmol) by slow bubbling through thesolution and taking weight difference of cannister. The mixture cooledwith a ice-water bath before H₂O₂ (2.45 mL of 30% w/v, 21.6 mmol) wasadded drop-wise over 10 min keeping temperature <23° C. The mixture wasallowed to stir for 15 min before it was poured onto ice (250 g)producing a white precipitate. The slurry was stirred for 5 min and thenthe solid was collected via filtration. The off-white solid was taken upin acetonitrile (150 mL) and was heated at reflux of 1 h. The solventwas removed and the solid was recrystallized from EtOH (15 mL/g) andwater (5 mL/g). The solid was collected and dried to give1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]sulfate(2.9 g, 33%). ESI-MS m/z calc. 308.1. found 309.1 (M+1)⁺; Retentiontime: 1.23 minutes (3 min run).

7-Chloro-1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]Step 1: tert-Butyl7-chloro-1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate

tert-Butyl7′-chlorospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(370 mg, 1.0 mmol), potassium carbonate (360 mg, 2.6 mmol) andtrifluoromethanesulfonate 5-(trifluoromethyl)dibenzothiophen-5-ium (1.0g, 2.5 mmol) were combined in N,N-dimethylformamide (3.7 mL). Thereaction mixture was heated at 80° C. for 90 minutes.Trifluoromethanesulfonate 5-(trifluoromethyl)dibenzothiophen-5-ium (200mg, 0.50 mmol) and potassium carbonate (69 mg, 0.50 mmol) were added andstirring was continued for an additional 40 minutes. The reactionmixture was partitioned between 50 mL of water and 50 mL ofdichloromethane. The layers were separated and the organic layer waswashed with a saturated aqueous solution of sodium chloride. The organiclayer was dried over sodium sulfate, filtered, and evaporated to drynessto yield a pale yellow solid. The crude material was purified on silicagel utilizing a gradient of 0-5% ethyl acetate in hexanes to yieldtert-butyl7-chloro-1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate(210 mg, 63%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, J=8.8Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 7.06 (dd, J=8.8, 2.4 Hz, 1H), 6.80 (d,J=3.9 Hz, 1H), 6.04 (d, J=3.9 Hz, 1H), 4.07-3.96 (m, 2H), 3.26-3.14 (m,2H), 2.07-1.81 (m, 4H), 1.47 (s, 9H). ES1-MS m/z calc. 442.9. found443.1 (M+1)⁺; Retention time: 2.34 minutes (3 min run).

Step 2:7-Chloro-1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]hydrochloricacid

tert-Butyl7-chloro-1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate(210 mg, 0.14 mmol) was dissolved in HCl in dioxane (2.0 mL of 4.0 M,8.0 mmol). The reaction mixture was allowed to stand for 30 minutes. Thereaction mixture was then evaporated to dryness to give7-chloro-1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]hydrochloricacid. ESI-MS m/z calc. 342.7. found 343.3 (M+1)⁺; Retention time: 1.46minutes (3 min run).

2-Methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] and3-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] Step1: 2-(3-Methyl-1H-pyrrol-1-yl)phenol

Diisobutylaluminum (100 mL of 1.0 M, 100 mmol) was added dropwise to asolution of dimethyl 2-methylbutanedioate (7.6 g, 48 mmol) indichloromethane (15 mL) at −78° C., and the solution was stirred for 1h. A suspension of 2-aminophenol HCl salt (6.6 g, 45 mmol) in water (110mL) was added initially dropwise with vigorous stirring, then in smallportions. About midway through the addition, the cooling bath wasremoved to help facilitate stirring. The mixture was stirred vigourouslyat room temperature overnight, then filtered over celite and the filtercake was washed several times with dichloromethane. The filtrate wasseparated, and the aqueous layer was extracted with dichloromethane(2×20 mL). The combined organics were washed with brine (50 mL), driedover MgSO₄, concentrated and purified by column chromatography (0-40%EtOAc/hexane) to give 2-(3-methylpyrrol-1-yl)phenol (3.7 g, 48%) as ayellow oil. ESI-MS m/z calc. 173.2. found 174.3 (M+1)⁺; Retention time:1.51 minutes (3 min run).

Step 2: tert-Butyl2-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylateand tert-butyl3-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate

To 2-(3-methylpyrrol-1-yl)phenol (2.0 g, 12 mmol) and tert-butyl4-oxopiperidine-1-carboxylate (2.5 g, 13 mmol) in dichloromethane (36mL) under N₂ was added, dropwise at 0° C., dichloroacetic acid (1.9 mL,23 mmol) over 5 min. The mixture was stirred at that temperature for 2 hthen held at 5° C. overnight. The mixture was washed with water (10 mL),1 M NaOH (20 mL) and brine (10 mL), dried over MgSO₄ and purified bycolumn chromatography (0-30% EtOAc/hexane) to give a mixture of productisomers (˜2.7 g, 68%, 2:1 ratio by NMR). The mixture, was subjected toSFC separation using ChiralPak OD-H (30% MeOH w/0.1% DEA, 70% CO₂) togive tert-butyl3-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidineF1′-carboxylateas the first eluting fraction (1.0 g, 37%) and tert-butyl2′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylateas the second eluting fraction (0.40 g, 30%).

Step 3a:3-Methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]hydrochloricacid

To tert-butyl2′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (second eluting fraction from step 2)(0.40 g, 1.1 mmol) was addedhydrogen chloride in 1,4-dioxane (2.8 mL of 4.0 M, 11 mmol) and themixture stirred 1 h, then filtered and rinsed with 1:1 ether/isopropanolto give 2′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]as a pink solid. ESI-MS m/z calc. 254.3. found 255.3 (M+1)⁺; Retentiontime: 1.16 minutes (3 min run).

Step 3b:3-Methylspiro[benzo[b]pyrrolo[1,2-d]11,4]oxazine-4,4′-piperidine]hydrochloricacid

To tert-butyl3-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate(first eluting peak from step 2 (1.0 g, 2.8 mmol) was added hydrogenchloride in 1,4-dioxane (7.0 mL of 4.0 M, 28 mmol) and the mixturestirred 1 h, then filtered and rinsed with 1:1 ether/isopropanol to give3′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] as a pinksolid. ESI-MS m/z calc. 254.3. found 255.3 (M+1)⁺; Retention time: 1.14minutes (3 min run).

2′-Methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]

Trifluoroacetic acid (443 μL, 5.75 mmol) was added to a solution of2-pyrrol-1-ylphenol (457 mg, 2.87 mmol) and tert-butyl2-methyl-4-oxo-piperidine-1-carboxylate (613 mg, 2.87 mmol) indichloromethane (19 mL) and the solution was vigorously stirred for 16h. The reaction mixture was quenched with saturated aqueous NaHCO₃, andthe organics were extracted with EtOAc (3×200 mL). The combined organicswere washed with water, brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (silicagel: 0-10% EtOAc in dichloromethane) to give tert-butyl2′-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylateas a brown oil. The crude residue was dissolved in a solution of HCl indioxane (1.4 mL of 4.0 M, 5.6 mmol) and stirred for 30 min at roomtemperature. The volatiles were removed in vacuo and the residue wasdissolved in diethylether. The solids were collected by filtration toprovide2′-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]hydrochloride(386 mg, 46%) as a reddish brown solid. ESI-MS m/z calc. 254.1. found255.5 (M+1)⁺; Retention time: 1.12 minutes (3 min run).

8′-Azaspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,3′-bicyclo[3.2.1]octane]Step 1: (1R,5S)-8-(2,2,2-Trifluoroacetyl)-8-azabicyclo[3.2.1]octan-3-one

A solution of (1S,5R)-8-azabicyclo[3.2.1]octan-3-one (500 mg, 4.00 mmol)in pyridine (16 mL) was stirred in an ice bath and(2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (1.11 mL, 7.99 mmol) wasadded dropwise. The solution was gently warmed to room temperature andstirred for 1 h. The reaction was then quenched with ice and wasextracted with EtOAc (3×100 mL). The organic layers were combined andwashed with saturated aqueous NaHCO₃, followed by 1M NaOH, and brine.The organic layer was dried over Na₂SO₄, filtered and concentrated toprovide (1R,5S)-8-(2,2,2-trifluoroacetyl)-8-azabicyclo[3.2.1]octan-3-oneas a clear oil (620 mg, 70%). ¹H NMR (400 MHz, CDCl₃) δ 5.08-4.94 (m,1H), 4.79-4.67 (m, 1H), 2.87-2.63 (m, 2H), 2.52 (d, J=16.2 Hz, 2H),2.35-2.08 (m, 2H), 2.01-1.86 (m, 1H), 1.85-1.73 (m, 1H).

Step 2:2,2,2-Trifluoro-1-(8′-azaspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,3′-bicyclo[3.2.1]octane]-8′-yl)ethanone

A solution of TFA (387 μL, 5.02 mmol) in dichloroethane (18 mL) wasadded to 2-pyrrol-1-ylphenol (401 mg, 2.52 mmol) and(1R,5S)-8-(2,2,2-trifluoroacetyl)-8-azabicyclo[3.2.1]octan-3-one (620mg, 2.80 mmol). The solution was heated at 70° C. overnight. The solventwas evaporated and the crude residue was purified by columnchromatography (silica gel: 0-10% EtOAc in hexanes) to afford2,2,2-trifluoro-1-(8′-azaspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,3′-bicyclo[3.2.1]octane]-8′-yl)ethanoneas a clear oil (469 mg, 46%). ¹H NMR (400 MHz, CDCl₃) δ 7.27 (d, J=7.5Hz, 1H), 7.07-6.94 (m, 4H), 6.23 (t, J=3.2 Hz, 1H), 5.87 (d, J=3.4 Hz,1H), 4.74 (d, J=7.4 Hz, 1H), 4.42 (s, 1H), 2.50-2.34 (m, 2H), 2.34-2.16(m, 3H), 2.16-1.89 (m, 3H). ESI-MS m/z calc. 362.4. found 363.3 (M+1)⁺;Retention time: 2.07 minutes (3 min run).

Step 3:8′-Azaspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,3′-bicyclo[3.2.1]octane]

To a solution of 2:2,2,2-trifluoro-1-(8′-azaspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,3′-bicyclo[3.2.1]octane]-8′-yl)ethanone(469 mg, 1.29 mmol) in MeOH (5 mL) was added NaOH (1.3 mL of 2.0 M, 2.6mmol). The solution was heated at 70° C. overnight. The reaction wasthen cooled to room temperature and the organics were extracted withEtOAc (3×100 mL), combined, and dried over Na₂SO₄. The organic layer wasthen filtered and concentrated to provide8′-azaspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,3′-bicyclo[3.2.1]octane]as an opaque oil in quantitative yield. ¹H NMR (400 MHz, CDCl₃) δ 7.28(d, J=7.7 Hz, 1H), 7.09-6.96 (m, 4H), 6.26 (t, J=3.2 Hz, 1H), 5.97 (d,J=3.4 Hz, 1H), 3.58 (s, 2H), 2.40-2.29 (m, 2H), 2.21-2.15 (m, 2H), 2.09(dd, J=15.0, 3.1 Hz, 2H), 1.86-1.77 (m, 2H). ESI-MS m/z calc. 266.3.found 267.3 (M+1)⁺; Retention time: 1.04 minutes (3 min run).

Spiro[piperidine-4,6′-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine]

A mixture of 2-pyrrol-1-ylpyridin-3-ol (1.00 g, 6.24 mmol), tert-butyl4-oxopiperidine-1-carboxylate (1.24 g, 6.24 mmol),4-methylbenzenesulfonic acid hydrate (119 mg, 0.625 mmol), molecularsieves (442 mg) and dichloroethane (8.9 mL) was heated at 130° C. for162 hours. The reaction was filtered and washed with dichloroethane. Thesolid was dissolved in MeOH and filtered through a plug of Celite. Thesolvent was evaporated under reduced pressure to yieldspiro[piperidine-4,6′-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine] (1.4 g,38%). ESI-MS m/z calc. 241.1. found 242.5 (M+1)⁺; Retention time: 1.10minutes (4 min run).

9′-(Trifluoromethyl)spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]Step 1: Benzylspiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate

To a stirred solution of 3-pyrrol-1-ylpyridin-2-ol (481 mg, 3.00 mmol)and benzyl 4,4-dimethoxypiperidine-1-carboxylate (922 g, 3.3 mol) inCH₂Cl₂ (20 mL) at 40° C. was added BF₃.OEt₂ (407.3 μL, 3.300 mmol)drop-wise. The reaction mixture was stirred at 40° C. for 16 hours. Themixture was poured into sat. aq. Na₂CO₃ and was stirred for 5 min beforeit was extracted with EtOAc (3×). Organic layers were combined, washedwith sat. aq. Na₂CO₃, water, brine, dried (Na₂ SO₄) and evaporated todryness. The residue was purified by column chromatography (1-30%EtOAc/CH₂Cl₂) to give benzylspiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylateas an oil. ESI-MS m/z calc. 375.2. found 376.5 (M+1)⁺; Retention time:1.70 minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 8.10 (dd, J=7.7, 1.1Hz, 1H), 8.00 (dd, J=4.9, 1.5 Hz, 1H), 7.60-7.52 (m, 1H), 7.42-7.36 (m,4H), 7.36-7.29 (m, 1H), 7.16 (dd, J=7.8, 4.9 Hz, 1H), 6.33 (t, J=3.2 Hz,1H), 6.20 (d, J=3.4 Hz, 1H), 5.11 (s, 2H), 3.97 (d br, J=13.2 Hz, 2H),3.28 (s br, 2H), 1.98-1.92 (m, 4H).

Step 2: tert-Butylspiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate

A solution of benzylspiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate(220 mg, 0.586 mmol), AcOH (33 μL, 0.59 mmol) and Pd/C (22 mg, 0.21mmol) in MeOH (2 mL) was stirred under a balloon on H₂ for 6 hours. Themixture was filtered through celite and the fitrate was evaporated togive spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine](ESI-MS m/z calc. 241.1. found 242.5 (M+1)⁺; Retention time: 0.46minutes (3 min run)). The residue was then taken up in THF (3 mL) beforeNa₂CO₃ (1.2 mL of 2.0 M, 2.4 mmol) was added. Boc₂O (156 mg, 0.70 mmol)was added and the mixture was stirred at room temperature for 12 hours.N,N-dimethylethylenediamine (0.5 mL) was added and the mixture wasstirred at room temperature for 30 min. The mixture was poured intowater and was extracted with EtOAc (3×). The organics were combined,washed with 0.1N HCl (3×), brine, dried (Na₂SO₄) and filtered through aplug of silica to give tert-butylspiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate(134 mg, 67%). ¹H NMR (400 MHz, DMSO) δ 8.18-8.13 (m, 1H), 8.12-8.00 (m,1H), 7.69-7.56 (m, 1H), 7.32-7.12 (m, 1H), 6.39 (dd, J=5.8, 3.0 Hz, 1H),6.33-6.20 (m, 1H), 3.94 (d, J=11.9 Hz, 2H), 3.26 (s, 2H), 2.02 (s br,4H), 1.48 (d, J=2.3 Hz, 9H).

Step 3: tert-Butyl9′-(trifluoromethyl)spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate

A solution of tert-butylspiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate(134 mg, 0.393 mmol) and 5-(trifluoromethyl)dibenzothiophen-5-ium (99.4mg, 0.393 mmol) in DMF (2 mL) was stirred at 80° C. for 1.5 hours. Themixture was poured into water and was extracted with EtOAc (3×). Theorganics were combined, washed with water and brine, dried (Na₂SO₄) andevaporated to dryness. The residue was purified by column chromatography(1-30% EtOAc/hexanes) to give tert-butyl9′-(trifluoromethyl)spiro-[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate(83 mg, 56%). ESI-MS m/z calc. 409.2. found 410.5 (M+1)⁺; Retentiontime: 1.92 minutes (3 min run).

Step 4:9′-(Trifluoromethyl)spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]

To a solution of tert-butyl9′-(trifluoromethyl)spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate(83 mg, 0.20 mmol) in CH₂Cl₂ (3 mL) was added TFA (1.0 mL, 13 mmol) andthe mixture was stirred at room temperature for 15 min before beingevaporated to dryness. The residue was taken up in EtOAc and sat. aq.Na₂CO₃, the layers were separated, and aqueous layer was extracted withEtOAc (2×). The organics were combined, washed with sat. aq. Na₂CO₃,brine, dried (Na₂SO₄) and evaporated to dryness to give9′-(trifluoromethyl)-spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]as a pale yellow solid solid (59 mg). ESI-MS m/z calc. 309.1. found310.3 (M+1)⁺; Retention time: 1.32 minutes (3 min run).

7-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehydeStep 1:1-(7-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)-2,2,2-trilluoroethanone

To a solution of7′-chlorospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (3.5 g,11.3 mmol) in dry THF (70.00 mL) at 0° C. was added Et₃N (6.27 mL, 45.0mmol) dropwise followed by DMAP (1.374 g, 11.25 mmol).(2,2,2-Trifluoroacetyl) 2,2,2-trifluoroacetate (2.82 mL, 20.3 mmol) wasadded and the mixture was stirred for 8 h at room temperature. Thesolvent was removed and the residue was partitioned between sat. aq.NaHCO₃ (50 mL) and DCM (250 mLl). The layers were separated and theaqueous phase was extracted with DCM (2×250 mL). The organics werecombined, dried, filtered, purified by column chromatography (3-15%AcOEt in hexanes) to give1-(7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)-2,2,2-trifluoroethanone(85%). ESI-MS m/z calc. 370.1. found 370.3 (M+1)⁺; Retention time: 2.15minutes (3 min run).

Step 2:7-Chloro-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde

POCl₃ (1.33 mL, 14.3 mmol) was added dropwise at 0° C. under N₂ to dryDMF (1.1 mL, 14 mmol). The reaction mixture was left for 20 min at thistemperature, which led to the formation of a white solid. A solution of1-(7′-chlorospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl)-2,2,2-trifluoro-ethanone(353 mg, 9.535 mmol) in dry DMF (26.5 mL) was added dropwise and thecooling bath was removed. The reaction was allowed to stir at roomtemperature for 1 h. The mixture was poured over ice and 1M NaOH (25 ml)was added. The pH was adjusted to 7 with 3M HCl and the mixture wasextracted with DCM three times. The combined organics were dried,filtered and concentrated. Column chromatography (5-30% AcOEt inhexanes) on the residue gave7-chloro-t-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde.ESI-MS m/z calc. 398.1. found 399.3 (M+1)⁺; Retention time: 1.96 minutes(3 min run).

Step 3:7-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde

To7′-chloro-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbaldehyde(510 mg, 1.28 mmol) dissolved in MeOH (5.1 mL) was added K₂CO₃ (371 mg,2.69 mmol) in one portion at room temperature. Water was added (2 mL),and organic solvent was removed under vacuum. The mixture was extractedwith DCM (3×10 mL). The organics were combined, dried, filtered, andconcentrated to give7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehydeas a yellow oil, which was used as is for the following step. ESI-MS m/zcalc. 302.1. found 303.3 (M+1)⁺; Retention time: 1.07 minutes (3 minrun).

1-Methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochlorideStep 1: tert-Butyl 4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (93.7 g, 470mmol) in pyrrolidine (56.0 mL, 673 mmol) and anhydrous MeOH (112 mL) wasadded 1-(2-hydroxyphenyl)ethanone (56 mL, 468 mmol). The reactionmixture was stirred at 80° C. for 2.5 hours. Methanol was removed underreduced pressure. The resulting residue was dissolved in ethyl acetate(150 mL), washed with 1 M aqueous HCl (1×150 mL) and brine (2×100 mL).The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford a yellow oil. This oil wasdiluted with hexane (400 mL) and was heated at 60° C. until in solution.Once dissolved, the solution was allowed to cool to 25° C. Crystals werecollected via vacuum filtration and rinsed with hexane to obtaintert-butyl 4-oxospiro[chromane-2,4′-piperidine]-1′-carboxylate (105 g,70%) as a light yellow solid. ES1-MS m/z calc. 317.2. found 318.2(M+1)⁺; Retention time: 1.78 minutes (3 min run). ¹H NMR (400 MHz,CDCl₃) δ 7.87 (dd, J=7.8, 1.5 Hz, 1H), 7.55-7.45 (m, 1H), 7.10-6.90 (m,2H), 3.95-3.80 (m, 2H), 3.26-3.17 (m, 2H), 2.72 (s, 2H), 2.03 (d, J=13.0Hz, 2H), 1.68-1.58 (m, 2H), 1.46 (s, 9H).

The following compounds were synthesized using the procedure describedabove: tert-butyl6-chloro-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate: ESI-MS m/zcalc. 351.1. found 352.4 (M+1)⁺; Retention time: 3.13 minutes (4 minrun). ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J=2.7 Hz, 1H), 7.44 (dd, J=8.8,2.7 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 3.92-3.83 (m, 2H), 3.24-3.13 (m,2H), 2.71 (s, 2H), 2.01 (d, J=12.7 Hz, 2H), 1.66-1.56 (m, 2H), 1.46 (s,9H); tert-butyl7-chloro-4-oxospiro-[chroman-2,4′-piperidine]-1′-carboxylate: ESI-MS m/zcalc. 351.1. found 352.2 (M+1)⁺; Retention time: 3.18 minutes (4 minrun). ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=8.4 Hz, 1H), 7.03 (d, J=1.8Hz, 1H), 6.99 (dd, J=8.4, 1.9 Hz, 1H), 3.94-3.83 (m, 2H), 3.25-3.16 (m,2H), 2.04-1.97 (m, 2H), 1.66-1.56 (m, 2H), 1.46 (s, 9H); tert-butyl6-methoxy-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate: ESI-MS m/zcalc. 347.2. found 348.4 (M+1)⁺; Retention time: 3.07 minutes (4 minrun). ¹H NMR (400 MHz, CDCl₃) δ 7.28 (dd, J=16.3, 2.4 Hz, 1H), 7.11 (dd,J=9.0, 2.6 Hz, 1H), 6.91 (dd, J=9.0, 2.0 Hz, 1H), 3.90-3.84 (m, 2H),3.80 (s, 3H), 3.26-3.15 (m, 2H), 2.69 (s, 2H), 2.07-1.97 (m, 2H),1.64-1.52 (m, 2H), 1.46 (s, 9H).

Step 2: tert-Butyl3-(diethoxymethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate

To triethyl orthoformate (85 mL, 510 mmol) in dry dichloromethane (460mL) under nitrogen at −10° C. was added dropwise BF₃.OEt₂ (65 mL, 510mmol). The solution was allowed to warm to 0° C. and was stirred for 10minutes. The solution was cooled to −78° C. prior to the slow dropwiseaddition of tert-butyl4-oxospiro[chromane-2,4′-piperidine]-1′-carboxylate (55 g, 170 mmol) indichloromethane (25 mL). N-ethyl-N-isopropylpropan-2-amine (100 mL, 600mmol) was added over a 30 minutes period, and the mixture was slowlywarmed to 25° C. and was stirred at this temperature overnight. Thereaction mixture was diluted with dichloromethane (500 mL) followed bysaturated aqueous sodium bicarbonate solution (500 mL). The layers wereseparated, and the organic layer was washed with additional sodiumbicarbonate (500 mL). The organic layer was dried over sodium sulfate,filtered and concentrated. The residue was purified by silica gel columnchromatography (0-25% ethyl acetate in hexane) to provide tert-butyl3-(diethoxymethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate(72 g, 91%) as an orange oil. ESI-MS m/z calc. 419.5. found 420.3(M+1)⁺; Retention time: 2.50 minutes (3 min run).

The following compounds were synthesized using the procedure describedabove: tert-butyl6-chloro-3-(diethoxymethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate:ESI-MS m/z calc. 453.2. found 454.4 (M+1)⁺; Retention time: 3.41 minutes(4 min run); tert-butyl7-chloro-3-(diethoxymethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate:ESI-MS m/z calc. 453.2. found 454.3 (M+1)⁺; Retention time: 2.41 minutes(3 min run); tert-butyl3-(diethoxymethyl)-6-methoxy-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate:ESI-MS m/z calc. 449.2. found 450.4 (M+1)⁺; Retention time: 3.28 minutes(4 min run).

Step 3:1-Methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride

To tert-butyl3-(diethoxymethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate(72 g, 160 mmol) was added hydrochloric acid (610 mL of 4.0 M, 2.5 mol).The reaction mixture was allowed to stir at 25° C. for 2 hours. Solventwas removed under vacuum, and the obtained solid was azeotroped withEtOH (3×700 mL). The resulting beige-white solid was dissolved in EtOH(685 mL) at 25° C. prior to the addition of tert-butylN-amino-N-methyl-carbamate (29 mL, 200 mmol). The solution was allowedto stir at 25° C. overnight. To the thick beige-white slurry that formedwas added hydrochloric acid (200 mL of 4.0 M, 800 mmol). The mixture washeated at 60° C. to yield a clear yellow solution. After 1 hour at 60°C., a thick white slurry developed. The slurry was allowed to slowlycool to 25° C., and solids were collected by vacuum filtration. Thefilter cake was rinsed with a 10% solution of EtOH in hexane (2×500 mL).The solid was placed in a vacuum oven overnight (20 mm Hg/45° C.).1-Methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride(42 g, 78%) was obtained as an off-white solid. ESI-MS m/z calc. 255.3.found 256.3 (M+1)⁺; Retention time: 1.30 minutes (3 min run). ¹H NMR(400 MHz, MeOD) δ 7.82-7.76 (m, 1H), 7.61 (s, 1H), 7.40-7.34 (s, 1H),7.22-7.14 (m, 2H), 4.19 (s, 3H), 3.52-3.42 (m, 2H), 3.41-3.33 (m, 2H),2.39-2.07 (m, 4H).

The following compounds were synthesized using the procedure describedabove:8-chloro-1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride:ESI-MS m/z calc. 289.1. found 290.3 (M+1)⁺; Retention time: 1.29 minutes(3 min run). ¹H NMR (400 MHz, DMSO) δ 7.74 (d, J=2.4 Hz, 1H), 7.43 (s,1H), 7.36 (dd, J=8.7, 2.4 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 4.12 (s, 3H),3.26-3.13 (m, 4H), 2.24-2.04 (m, 4H);7-chloro-1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride:ESI-MS m/z calc. 289.1. found 290.2 (M+1)⁺; Retention time: 2.00 minutes(4 min run). ¹H NMR (400 MHz, CDCl₃) δ 7.50 (d, J=8.3 Hz, 1H), 7.36 (s,1H), 7.17-6.97 (m, 2H), 4.15 (s, 3H), 3.48-3.37 (m, 4H), 2.45-2.22 (m,4H);8-methoxy-1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride:ESI-MS m/z calc. 285.2. found 286.5 (M+1)⁺; Retention time: 1.14 minutes(3 min run). NMR (400 MHz, CDCl₃) δ 7.36 (s, 1H), 7.12 (d, J=2.7 Hz,1H), 7.01 (d, J=8.9 Hz, 1H), 6.87-6.79 (m, 1H), 4.16 (s, 3H), 3.83 (s,3H), 3.48-3.39 (m, 4H), 2.48-2.18 (m, 4H).

2-Methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochlorideStep 1: (Z)-3-(ethoxymethylene)spiro[chroman-2,4′-piperidin]-4-onehydrochloride

To tert-butyl3-(diethoxymethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate(33.0 g, 78.7 mmol) in toluene (73.33 mL) was added hydrochloric acid(68.8 mL of 4.0 M in dioxane, 275 mmol). The reaction mixture was heatedat 60° C. for 15 min. Most of the solvent was removed under vacuum, andthe tan slurry was filtered using a medium frit. The solids were washedwith 500 mL of toluene. The solids were dried to give(Z)-3-(ethoxymethylene)spiro[chroman-2,4′-piperidin]-4-one hydrochloride(15.4 g, 63%). ESI-MS m/z calc. 273.1. found 274.3 (M+1)⁺; Retentiontime: 0.85 minutes (3 min run).

Step 2:2-Methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride

(Z)-3-(Ethoxymethylene)spiro[chroman-2,4′-piperidin]-4-one hydrochloride(2.46 g, 7.94 mmol) in ethanol (24.6 mL) was treated withmethylhydrazine (423 μL, 7.94 mmol). The reaction mixture was heated at70° C. for 1 h and then at 100° C. for 10 min. The mixture was allowedto cool to room temperature overnight. The yellow solid was filtered offand was washed with ethanol to give2-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride(1.20 g, 74%). ESI-MS m/z calc. 255.1. found 256.3 (M+1)⁺; Retentiontime: 0.65 minutes. ¹H NMR (400 MHz, DMSO) δ 9.01 (s, 2H), 7.75 (s, 1H),7.61 (dd, J=7.5, 1.2 Hz, 1H), 7.28-7.20 (m, 1H), 7.10-6.99 (m, 2H), 3.89(s, 3H), 3.28-3.18 (m, 4H), 2.18-2.02 (m, 4H).

2-(Trifluoromethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]Step 1: tert-Butyl1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate

To tert-butyl3-(diethoxymethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate(15.1 g, 35.9 mmol) and hydrazine (1.35 mL, 43.1 mmol) in EtOH (120 mL)was added hydrochloric acid (900 μL of 4.0 M in dioxanes, 3.6 mmol). Themixture was heated at 60° C. for 2 h before it was cooled and thesolvent was evaporated. The residue was purified by silica gelchromatography eluting with 0-100% ethyl acetate in hexanes to givetert-butyl spiro[lH-chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (8.76 g, 71%).ESI-MS m/z calc. 341.2. found 342.3 (M+1)⁺; Retention time: 1.69 minutes(3 min run).

Step 2: tert-Butyl2-(bromodifluoromethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylateand tert-butyl1-(bromodifluoromethyl)-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate

A solution of tert-butylspiro[1H-chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (1.80g, 5.26 mmol) in DMF (4.4 mL) was cooled to 0° C. Sodium hydride (242mg, 6.05 mmol) was added and the reaction mixture was stirred for 30min. Dibromodifluoromethane (11.0 g, 4.78 mL, 52.6 mmol) was added andthe reaction mixture was allowed to warm to room temperature over 2 h.The mixture was poured into water and was extracted withdichloromethane. The organics were washed with brine, dried over sodiumsulfate and evaporated. The crude material was purified by silica gelchromatography eluting with 100% dichloromethane until the first peakeluted then 0-10% ethyl acetate in dichloromethane to collect the secondpeak. Peak 1: tert-butyl2-[bromo(difluoro)methyl]spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate(251 mg, 10%). ESI-MS m/z calc. 469.1. found 470.5 (M+1)⁺; Retentiontime: 2.30 minutes (3 min run). Peak 2: tert-butyl1-[bromo(difluoro)methyl]spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate(200 mg, 8%). ESI-MS m/z calc. 469.1. found 470.3/472.3 (M+1)⁺;Retention time: 1.69 minutes (3 min run).

Step 3:2-(Trifluoromethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]

tert-butyl2-[bromo(difluoro)methyl]spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate(251 mg, 0.534 mmol) was dissolved in 2-isopropoxypropane (377 μL) at 0°C. before pyridine hydrofluoride (250 μL, 2.78 mmol) was added. Thereaction mixture was stirred for 15 min and oxomercury (98.3 mg, 0.454mmol) was added in three portions. The reaction was warmed to 25° C. andwas stirred for 16 h. The reaction mixture was poured into water and wasextracted with dichloromethane. The organics were washed with sodiumbicarbonate and brine, dried over sodium sulfate, and concentrated underreduced pressure to give a mixture of2-(trifluoromethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine](ESI-MS m/z calc. 309.1. found 310.5 (M+1)⁺; Retention time: 1.22minutes (3 min run)) and1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine].1-(Trifluoromethyl)-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]was also prepared using the procedure described above. ESI-MS m/z calc.309.1. found 310.5 (M+1)⁺;Retention time: 1.07 minutes (3 min run)

1,3-Dimethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochlorideStep 1: tert-Butyl3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate

To a solution of N-isopropylpropan-2-amine (0.57 mL, 4.1 mmol) in THF(3.5 mL) was added a solution of n-butyllithium in hexane (2.6 mL of 1.6M, 4.1 mmol) dropwise at −78° C. under Ar. The solution was allowed tostir at −20° C. for 15 min and then cooled to −78° C. tert-Butyl4-oxospiro[chromane-2,4′-piperidine]-1′-carboxylate (1.1 g, 3.5 mmol) inTHF (3.5 mL) was added at −78° C. followed by the addition ofacetaldehyde (0.22 mL, 3.9 mmol) in THF (3 mL). The reaction wasquenched with saturated aqueous ammonium chloride at −78° C., warmed to25° C. and extracted with ethyl acatate (2×). The combined organiclayers were washed with brine, dried over MgSO₄ and concentrated todryness. Purification by silica gel chromatography (20-30% ethyl acetatein hexane) provided tert-butyl3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate(0.80 g, 63%) as a colorless oil. ESI-MS m/z calc. 361.2. found 362.5(M+1)⁺; Retention time: 1.79 minutes (3 min run). ¹H NMR (400 MHz,CDCl₃) δ 7.87 (dd, J=7.8, 1.6 Hz, 1H), 7.55-7.48 (m, 1H), 7.06-6.96 (m,2H), 4.33-4.23 (m, 1H), 4.10-3.93 (m, 1H), 3.88-3.67 (m, 1H), 3.41-3.27(m, 1H), 3.07-2.94 (m, 1H), 2.62 (d, J=5.2 Hz, 1H), 2.45 (d, J=8.5 Hz,1H), 2.20-2.00 (m, 2H), 1.85-1.76 (m, 1H), 1.58-1.49 (m, 1H), 1.46 (s,9H), 1.26 (t, J=7.1 Hz, 1H) 1.13 (d, J=6.6 Hz, 3H).

Step 2: tert-Butyl3-acetyl-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate

A mixture of tert-butyl3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate(600 mg, 1.66 mmol) and Dess-Martin periodinane (8.3 mL of 0.30 M, 2.5mmol) was stirred at 25° C. for 5 h. The reaction mixture was dilutedwith dichloromethane, washed with saturated aqueous NaHCO₃ (2×), 5%Na₂S₂O₃ (2×), brine, dried over MgSO₄, filtered and concentrated todryness. Purification by silica gel chromatography provided tert-butyl3-acetyl-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (435 mg,73%). ESI-MS m/z calc. 359.2. found 360.4 (M+1)⁺; Retention time: 2.84minutes (4 min run). ¹H NMR (400 MHz, CDCl₃) δ 7.86 (dd, J=7.8, 1.5 Hz,1H), 7.60-7.52 (m, 1H), 7.07-7.01 (m, 2H), 4.10-3.79 (m, 2H), 3.76 (s,1H), 3.29-3.03 (m, 2H), 2.27 (s, 3H), 2.10-1.85 (m, 3H), 1.68-1.58 (m,1H), 1.47 (s, 9H).

Step 3:1,3-Dimethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride

A mixture of tert-butyl3-acetyl-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (250 mg,0.70 mmol), tert-butyl N-amino-N-methyl-carbamate (120 μL, 0.84 mmol)and p-toluene sulfonic acid monohydrate (27 mg, 0.14 mmol) in ethanol (8mL) was heated at 80° C. overnight. Additional tert-butylN-amino-N-methyl-carbamate (120 μL, 0.84 mmol) was added and the mixturewas heated at 80° C. for 6.5 h, then another portion of tent-butylN-amino-N-methyl-carbamate (120 μL, 0.84 mmol) was added and the mixturewas heated at 80° C. for 2 h. HCl (0.87 mL of 4.0 M in dioxane, 3.5mmol) was added and the mixture was stirred at 80° C. for 1 h. Aftercooling, the precipitate was collected via filtration and washed withcold EtOH to provide1,3-dimethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride(295 mg, >100%, may contain some methyl hydrazine HCl salt) as a solid.ESI-MS m/z calc. 269.2. found 270.5 (M+1)⁺; Retention time: 1.11 minutes(3 min run). ¹H NMR (400 MHz, DMSO) δ 7.71 (dd, J=7.8, 1.3 Hz, 1H),7.33-7.27 (m, 1H), 7.17-7.14 (m, 1H), 7.11-7.05 (m, 1H), 4.02 (s, 3H),3.28-3.15 (m, 4H), 2.40-2.30 (m, 2H), 2.23 (s, 3H), 2.07-1.97 (m 2H).

1H-Spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] Step 1: Benzyl4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate

A mixture of 1-(2-hydroxyphenyl)ethanone (50 g, 0.37 mol), benzyl4-oxopiperidine-1-carboxylate (94 g, 0.40 mol), pyrrolidine (61 mL, 0.73mol) and methanol (24 mL) was heated at 80° C. for 20 hours. Aftercooling to 25° C., the reaction mixture was diluted with ethyl acetate(1000 mL) and partitioned with 1M aqueous HCl (500 mL). The organicphase was washed with 1M aqueous HCl (2×500 mL), water (500 mL),saturated sodium chloride solution (500 mL), dried over magnesiumsulfate, filtered and concentrated. Purification by silica gelchromatography (0-30% ethyl acetate in hexane) afforded benzyl4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (105 g, 81% yield) asa yellow oil. ESI-MS m/z calc. 351.2. found 352.2 (M+1)⁺; Retentiontime: 2.30 minutes (3 min run). NMR (400 MHz, CDCl₃) δ 7.88 (d, J=7.8Hz, 1H), 7.54-7.47 (m, 1H), 7.44-7.29 (m, 5H), 7.02 (dd, J=14.8, 7.8 Hz,2H), 5.16 (s, 2H), 4.10-3.90 (m, 2H), 3.36-3.24 (m, 2H), 2.73 (s, 2H),2.12-2.00 (m, 2H), 1.71-1.58 (m, 2H).

Step 2: Benzyl3-(diethoxymethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate

To a solution of triethyl orthoformate (71 mL, 0.43 mol)] indichloromethane (250 mL) at −10° C. under nitrogen was added borontrifluoride diethyletherate (54 mL, 0.43 mol) dropwise over 30 minutes.The mixture was allowed to warm to 0° C. and stirring was continued at0° C. for 15 minutes. The mixture was then cooled to −78° C. and asolution of benzyl 4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate(50 g, 0.14 mol) in dichloromethane (250 mL) was added dropwise over 1hour, followed by N-ethyl-N-isopropylpropan-2-amine (87 mL, 0.50 mol)over 1 hour at −78° C. The mixture was continued to stir at −78° C. for30 minutes and then at 25° C. for 15 hours. The reaction mixture wasdiluted with dichloromethane (750 mL) and then partitioned withsaturated sodium bicarbonate solution (500 mL). The organic phase waswashed with water (500 mL), saturated sodium chloride solution (500 mL),dried over magnesium sulfate and concentrated under reduced pressure.Purification by silica gel flash chromatography (0-50% ethyl acetate inhexane) afforded benzyl3-(diethoxymethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate(50 g, 78%) as a yellow oil. ESI-MS m/z calc. 453.2. found 408.5(M+1-OEt)⁺; Retention time: 2.08 minutes (3 min run).

Step 3: Benzyl3-(hydroxymethylene)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate

Iodine (2.88 g, 11.4 mmol) was slowly added to a solution of benzyl3-(diethoxymethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate(20.6 g, 45.4 mmol) in acetone (515 mL) and the mixture was stirred at35° C. overnight. The reaction mixture was concentrated and the residuewas purified by silica gel column chromatography (0-40% ethyl acetate inhexane) to afford benzyl3-(hydroxymethylene)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate(15.2 g, 88%). ESI-MS m/z calc. 379.1. found 380.3 (M+1)⁺;

Retention time: 2.00 minutes (3 min run).

Step 4: Benzyl1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate

A solution of benzyl3-(hydroxymethylene)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate(1.95 g, 5.10 mmol) and hydrazine (161 μL, 5.10 mmol) in EtOH (39 mL)was stirred at room temperature for 1 hour and then at 50° C. for 3hours. The reaction mixture was concentrated and the residue waspurified by silica gel chromatography (10-100% ethyl acetate in hexane)to afford benzyl1H-spiro[chromeno-[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (1.11g, 58%). ESI-MS m/z calc. 375.2. found 376.3 (M+1)⁺;

Retention time: 1.71 minutes (3 min run).

Step 5: 1H-Spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]

A mixture of benzylspiro[1H-chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (1.11g, 2.96 mmol) and palladium (10% wt on carbon, 157 mg, 0.15 mmol) inMeOH (15 mL) was set under hydrogen (1 atm) and stirred vigorously atroom temperature for 3 hours. The reaction mixture was filtered throughCelite and the filtrate was concentrated to afford1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (570 mg, 80%). ESI-MSm/z calc. 241.1. found 242.5 (M+1)⁺; Retention time: 0.42 minutes (3 minrun).

1-(2-Methoxyethyl)-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochlorideStep 1: tert-Butyl3-(hydroxymethylene)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate

NaH (1.89 g, 47.3 mmol) was added in small portions to a mixture oftert-butyl 4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (3.0 g,9.5 mmol), Et₂O (75 mL), and MeOH (120 μL) at rt. The mixture wasallowed to stir for 1 h before ethyl formate (9.2 mL, 110 mmol) wasadded dropwise. The mixture was allowed to stir at 25° C. overnightbefore it was quenched with 1M aqueous HCl. The layers were separatedand the aqueous layer was extracted with ethyl acetate (3×). Thecombined organics were washed with brine, dried over sodium sulfate, andconcentrated in vacuo. Column chromatography (0-100% ethyl acetate inhexanes) provided tert-butyl3-(hydroxymethylene)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate(1.2 g, 36%) as a light yellow solid. ESI-MS m/z calc. 345.2. found246.2 (M+1-Boc)⁺; Retention time: 2.62 minutes (4 min run). ¹H NMR (400MHz, CDCl₃) δ 15.13 (d, J=8.3 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.88 (dd,J=7.8, 1.5 Hz, 1H), 7.50-7.44 (m, 1H), 7.06 (t, J=7.5 Hz, 1H), 6.96 (d,J=8.2 Hz, 1H), 4.10-3.95 (m, 2H), 3.25-3.15 (m 2H), 2.15 (d, J=12.7 Hz,2H), 1.80-1.66 (m, 2H), 1.47 (s, 9H).

Step 2:1-(2-Methoxyethyl)-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride

A mixture of tert-butyl3-(hydroxymethylene)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate(200 mg, 0.58 mmol) and tert-butyl N-amino-N-(2-methoxyethyl)carbamate(130 mg, 0.70 mmol) in ethanol (5 mL) was allowed to stir at rt for 2 h.A solution of hydrogen chloride in 1,4-dioxane (150 μL of 4.0 M, 0.60mmol) was added and the mixture was stirred at 50° C. for 1.5 h beforeit was concentrated in vacuo to give1-(2-methoxyethyl)-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride(85 mg, 44%). ESI-MS m/z calc. 299.2. found 300.3 (M+1)⁺; Retentiontime: 0.95 minutes (3 min run).

1-(2,2,2-Trifluoroethyl)-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]and2-(2,2,2-trifluoroethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]

A mixture of tert-butyl3-(hydroxymethylene)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate(100 mg, 0.29 mmol) and 2,2,2-trifluoroethylhydrazine (57 mg, 0.35 mmol)in ethanol (2.5 mL) was allowed to stir at 25° C. for 2 h. A solution ofhydrogen chloride in 1,4-dioxane (72 μL of 4.0 M, 0.29 mmol) was addedand the mixture was stirred at 50° C. for 1.5 h before it wasconcentrated in vacuo to give a mixture of1-(2,2,2-trifluoroethyl)-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]and2-(2,2,2-trifluoroethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine](60 mg, 58%). ESI-MS m/z calc. 323.1. found 324.2 (M+1)⁺; Retentiontime: 1.11 minutes (3 min run).

(4-tert-Butyl-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanoneand(4-tert-butyl-3-methoxyphenyl)(2-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanoneStep 1: 1-(4-tert-Butyl-3-methoxybenzoyl)piperidin-4-one

A solution of 4-tert-butyl-3-methoxybenzoyl chloride (650 mg, 4.2 mmol)in toluene (4.4 mL) and a solution of NaOH (1.1 mL of 4.0 M, 4.4 mmol)were contemporaneously added dropwise to a solution of4-tert-butyl-3-methoxybenzoyl chloride (960 mg, 4.2 mmol) in NaOH (2.1mL of 2.0 M, 4.2 mmol) at 25° C. The mixture was stirred for 90 minbefore the toluene was removed in vacuo. The alkaline phase wasextracted with dichloromethane (3×). The organics were combined, washedwith brine, dried over sodium sulfate, and concentrated in vacuo toprovide 1-(4-tert-butyl-3-methoxybenzoyl)-piperidin-4-one (1.2 g, 94%).ESI-MS m/z calc. 289.2. found 290.3 (M+1)⁺; Retention time: 1.60 minutes(3 min run).

Step 2:1′-(4-tert-Butyl-3-methoxybenzoyl)spiro[chroman-2,4′-piperidin]-4-one

1-(2-Hydroxyphenyl)ethanone (260 μL, 2.2 mmol) was added portion-wise atroom temperature to pyrrolidine (370 μL, 4.4 mmol) followed byportion-wise addition of1-(4-tert-butyl-3-methoxy-benzoyl)piperidin-4-one (630 mg, 2.2 mmol).Anhydrous methanol (140 μL) was added and the slurry was heated at 80°C. for 3 h. The mixture was then partitioned between ethyl acetate and1M aqueous HCl. The layers were separated and the aqueous layer wasdiscarded. Saturated aqueous sodium bicarbonate was added and the layerswere separated. The organic layer was washed with brine, dried oversodium sulfate, and concentrated under reduced pressure. The residue waspurified by column chromatography (0-25% ethyl acetate/hexanes) to give1′-(4-tert-butyl-3-methoxybenzoyl)spiro[chroman-2,4′-piperidin]-4-one(840 mg, 94%) as a light yellow solid. ESI-MS m/z calc. 407.2. found408.2 (M+1)⁺; Retention time: 2.07 minutes (3 min run).

Step 3:1′-(4-tert-Butyl-3-methoxybenzoyl)-3-(hydroxymethylene)-spiro[chroman-2,4′-piperidin]-4-one

NaH (57 mg, 1.4 mmol) was added in small portions to a mixture of1′-(4-tert-butyl-3-methoxy-benzoyl)spiro[chromane-2,4′-piperidine]-4-one(250 mg, 0.61 mmol) in THF (2.5 mL) at 25° C. A solution of ethylformate (74 μL, 0.90 mmol) in THF (0.5 mL) was added and the mixture wasallowed to stir at 25° C. for 3 h before it was quenched with 0.5Maqueous HCl. The layers were separated and the aqueous layer wasextracted with ethyl acetate (3×). The combined organics were washedwith brine, dried over sodium sulfate, and concentrated in vacuo toprovide1′-(4-tert-butyl-3-methoxybenzoyl)-3-(hydroxymethylene)spiro[chroman-2,4′-piperidin]-4-one(50 mg, 19%) as an orange oil. ESI-MS m/z/z calc. 435.2. found 436.2(M+1)⁺; Retention time: 1.87 minutes (3 min run).

Step 4:(4-tert-Butyl-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanoneand(4-tert-butyl-3-methoxyphenyl)(2-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone

A mixture of1′-(4-tert-butyl-3-methoxy-benzoyl)-3-(hydroxymethylene)-spiro[chromane-2,4′-piperidine]-4-one(50 mg, 0.12 mmol) and methylhydrazine (6.7 μL, 0.13 mmol) in ethanol(1.6 mL) was allowed to stir at 25° C. for 3 h. The mixture was filteredand then purified by reverse phase HPLC to provide(4-tert-butyl-3-methoxy-phenyl)-(2-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(8 mg, 15%) (peak 1) and(4-tert-butyl-3-methoxy-phenyl)-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(peak 2).(4-tert-Butyl-3-methoxy-phenyl)-(2-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone:ESI-MS m/z calc. 445.2. found 446.3 (M+1)⁺; Retention time: 1.87 minutes(3 min run). ¹H NMR (400 MHz, CDCl₃) δ 7.56 (s, 1H), 7.33 (t, J=7.5 Hz,1H), 7.2-7.20 (m, 1H), 7.17-7.10 (m, 1H), 7.06-6.94 (m, 2H), 6.93-6.83(m, 2H), 4.25-4.05 (m, 1H), 4.02-3.93 (m, 1H), 3.85-3.75 (m, 1H), 3.79(s, 3H), 3.63 (s, 3H), 3.55-3.40 (m, 1H), 2.37-2.18 (m, 2H), 1.35 (s,9H), 1.30-1.15 (m, 2H).(4-tert-Butyl-3-methoxy-phenyl)-(1-methylspiro-[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yOmethanone:ESI-MS m/z calc. 445.2. found 446.3 (M+1)⁺; Retention time: 2.10 minutes(3 min run). ¹H NMR (400 MHz, CDCl₃) δ 7.50 (d, J=7.5 Hz, 1H), 7.32-7.25(m, 2H), 7.18 (t, J=7.7 Hz, 1H), 7.08-6.88 (m, 3H), 6.84 (t, J=7.5 Hz,1H), 4.43-4.32 (m, 1H), 4.20-4.05 (m, 1H), 3.93 (s, 3H), 3.84 (s, 3H),3.76-3.55 (m, 2H), 2.26-2.25 (m, 2H), 1.80-1.50 (m, 2H), 1.36 (s, 9H).

(4-Methoxy-3-(trifluoromethyl)phenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanoneStep 1: 1-(4-Methoxy-3-(trifluoromethyl)benzoyl)piperidin-4-one

A solution of 4-methoxy-3-(trifluoromethyl)benzoyl chloride (4.00 g,16.8 mmol) in toluene (16 mL) and a solution of NaOH (3.8 mL of 4.0 M,15 mmol) were contemporaneously added drop-wise to a solution ofpiperidine-4,4-diol hydrochloride (2.30 g, 15.2 mmol) in NaOH (7.6 mL of2.0 M, 15 mmol) at 25° C. The mixture was stirred for 90 min before thetoluene was removed in vacuo. The alkaline phase was extracted withdichloromethane (3 times). The organics were combined, washed withbrine, dried over Na₂SO₄, and concentrated in vacuo to provide1-(4-methoxy-3-(trifluoromethyl)benzoyl)piperidin-4-one (4.2 g, 91%).ESI-MS m/z calc. 301.3. found 302.2 (M+1)⁺. Retention time: 0.95 minutes(3 min run). NMR (400 MHz, CDCl₃) δ 7.77 (d, J=1.9 Hz, 1H), 7.70 (dd,J=8.6, 2.1 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 4H),2.55 (s, 4H).

Step 2:1′-(4-Methoxy-3-(trifluoromethyl)benzoyl)spiro[chroman-2,4′-piperidin]-4-one

1-(2-Hydroxyphenyl)ethanone (1.80 g, 13.3 mmol) was added portion wiseat 25° C. to pyrrolidine (2.20 mL, 26.6 mmol) followed by portion-wiseaddition of 1-(4-methoxy-3-(trifluoromethyl)benzoyl)piperidin-4-one(4.00 g, 13.3 mmol). Anhydrous methanol (868 μL) was then added and thered slurry was heated at 80° C. for 3 hours. The reaction was cooled to25° C. and was stirred overnight. Ethyl acetate (5 mL) and 1M HCl (aq, 5mL) were added. The aqueous layer was separated and discarded. 1M NaOH(aq, 5 mL) was added and the aqueous layer was separated and discarded.A brine solution was added (10 mL) and the aqueous layer was separatedand discarded. The organic layer was dried over Na₂SO₄, filtered and thesolvent was evaporated to provide an oil. The crude oil was dissolved indichloromethane and was purified by column chromatography using 0-50%ethyl acetate/hexanes to provide1′-(4-methoxy-3-(trifluoromethyl)benzoyl)spiro[chroman-2,4′-piperidin]-4-one(4.4 g, 79%) as a off-white solid. ES1-MS m/z calc. 419.4. found 420.2(M+1)⁺. Retention time: 2.63 minutes (4 min run).

Step 3:(Z)-3-(Hydroxymethylene)-1′-(4-methoxy-3-(trifluoromethyl)benzoyl)spiro[chroman-2,4′-piperidin]-4-one

NaH (120 mg, 3.0 mmol) was added to a mixture of1′-(4-methoxy-3-(trifluoromethyl)benzoyl)spiro[chroman-2,4′-piperidin]-4-one (250 mg, 0.60 mmol) indiethyl ether (6.2 mL) at 0° C. MeOH (0.01 mL) was added and the mixturewas allowed to warm to 25° C. over 1 h. The mixture was cooled to 0° C.before ethyl formate (600 μL, 7.4 mmol) was added slowly. The mixturewas allowed to stir at 25° C. overnight. The mixture was slowlypartitioned between ethyl acetate and water. The layers were separatedand the aqueous layer was extracted with ethyl acetate (twice). Thecombined organics were washed with brine, dried over sodium sulfate, andconcentrated in vacuo to yield a crude mixture containing the desiredproduct that was taken to the next step without further purification.ESI-MS m/z calc. 447.4. found 448.1 (M+1)⁺. Retention time: 2.38 minutes(4 min run).

Step 4:(4-Methoxy-3-(trifluoromethyl)phenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone

tert-Butyl N-amino-N-methyl-carbamate (21 mg, 0.14 mmol) was added to amixture of(Z)-3-(hydroxymethylene)-1′-(4-methoxy-3-(trifluoromethyl)benzoyl)spiro[chroman-2,4′-piperidin]-4-one(53 mg, 0.12 mmol) in ethanol (1.6 mL) at 25° C. The mixture was allowedto stir at 25° C. for 2 hours before hydrogen chloride (150 μL of 4.0 M,0.60 mmol) was added. The mixture was heated at 50° C. for 1 h before itwas cooled to 25° C. and concentrated in vacuo. The residue was taken upin DMF and was purified by reverse phase HPLC to give(4-methoxy-3-(trifluoromethyl)phenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone.ESI-MS m/z calc. 457.2. found 458.1 (M+1)⁺. Retention time: 2.66 minutes(4 min run). ¹H NMR (400 MHz, CDCl₃) δ 7.73 (s, 1H), 7.68 (d, J=8.5 Hz,1H), 7.62 (d, J=6.8 Hz, 1H), 7.43 (s, 1H), 7.36 (t, J=7.2 Hz, 1H),7.16-7.03 (m, 3H), 4.30 (s, 3H), 3.97 (s, 3H), 3.51 (s, 2H), 2.73 (s,2H), 2.16 (s, 2H), 1.92 (s, 2H).

(4-Methoxy-3-(trifluoromethyl)phenyl)(1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone

A mixture of3-(hydroxymethylene)-1′-[4-methoxy-3-(trifluoromethyl)-benzoyl]spiro[chromane-2,4′-piperidine]-4-one(54 mg, 0.12 mmol) and hydrazine (3.8 μL, 0.12 mmol) in ethanol (1.7 mL)was allowed to stir for 1 h at 25° C., then for 2.5 h at 50° C. Themixture was cooled and then concentrated in vacuo. The residue was takenup in DMF and was purified by reverse phase HPLC to give(4-methoxy-3-(trifluoromethyl)phenyl)(1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone.ESI-MS m/z calc. 443.2. found 444.1 (M+1)⁺; Retention time: 2.40 minutes(4 min run). ¹H NMR (400 MHz, CDCl₃) δ 9.15-8.90 (m, 1H), 7.73 (s, 1H),7.67 (d, J=8.3 Hz, 1H), 7.58 (s, 1H), 7.52 (d, J=7.7 Hz, 1H), 7.33-7.18(m, 1H), 7.04 (dd, J=18.8, 8.3 Hz, 2H), 6.91 (t, J=7.5 Hz, 1H),6.05-5.60 (m, 1H), 4.50-4.05 (m, 2H), 4.08-3.55 (m, 3H), 3.97 (s, 3H),2.50-2.32 (m, 2H).

1-Ethyl-/H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] Step 1:tert-Butyl 1,3-dioxoisoindolin-2-yl(ethyl)carbamate

tert-Butyl N-(1,3-dioxoisoindolin-2-yl)carbamate (1.0 g, 3.8 mmol),iodoethane (460 μL, 5.7 mmol), potassium carbonate (2.1 g, 15 mmol), andbenzyl-triethyl-ammonium bromide (210 mg, 0.80 mmol) were combined inacetonitrile (15 mL) and heated at 50° C. for 48 h. The reaction mixturewas diluted with water (30 mL) and was extracted with ether (3×15 mL).The combined organics were washed with brine, dried over sodium sulfateand evaporated to dryness. The crude material was purified by columnchromatography (0-20% ethyl acetate in hexanes) to afford tert-butyl1,3-dioxoisoindolin-2-yl(ethyl)-carbamate (0.79 g, 71%). ESI-MS m/zcalc. 290.1. found 291.3 (M+1)⁺; Retention time: 1.64 minutes (3 minrun). ¹H NMR (400 MHz, CDCl₃) δ 7.98-7.85 (m, 2H), 7.84-7.69 (m, 2H),3.86-3.57 (m, 2H), 1.52 (s, 3H), 1.32 (s, 6H), 1.27-1.04 (m, 3H).

Step 2: tert-Butyl 1-ethylhydrazinecarboxylate

tert-Butyl 1,3-dioxoisoindolin-2-yl(ethyl)-carbamate (790 mg, 2.7 mmol)in THF (16 mL) was cooled to 0° C. and methylhydrazine (250 μL, 4.8mmol) was added. The reaction mixture was warmed to room temperature andwas stirred until all starting material was consumed. The mixture wasfiltered through a pad of Celite and the solvent was evaporated. Theresidue was purified by column chromatography (0-10% methanol indichloromethane) to afford tert-butyl 1-ethylhydrazinecarboxylate (320mg, 74%). Retention time: 1.13 minutes (3 min run).

Step 3: Benzyl1-ethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate

A mixture of tert-butyl 1-ethylhydrazinecarboxylate (320 mg, 2.0 mmol)and benzyl3-(hydroxymethylene)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate(770 mg, 2.0 mmol) in dichloroethane (5 mL) was allowed to stir at 25°C. with TFA (78 μL, 1.0 mmol) for 2 h. Once LC/MS analysis showedcomplete imine formation, more TFA was added to deprotect the hydrazineand cyclize the product. The reaction was diluted with dichloromethane,and aqueous sodium bicarbonate was added with stirring. The layers wereseparated and the organics were further washed with saturated aqueoussodium bicarbonate and brine. The organics were dried over sodiumsulfate and evaporated to dryness. The crude material was purified bycolumn chromatography (0-100% ethyl acetate in hexanes) to afford benzyl1-ethyl-1H-spiro[chromeno[4,3:c]pyrazole-4,4′-piperidine]-1′-carboxylate(530 mg, 65%). ESI-MS m/z calc. 403.2. found 404.7 (M+1)⁺; Retentiontime: 1.94 minutes (3 min run). ¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J=7.6Hz, 1H), 7.40-7.29 (m, 4H), 7.29-7.19 (m, 2H), 7.10-6.99 (m, 2H), 5.16(s, 2H), 4.47 (q, J=7.3 Hz, 2H), 4.15-3.95 (m, 2H), 3.45-3.26 (m, 2H),2.15-2.03 (m, 2H), 1.88-1.78 (m 2H), 1.54 (t, J=7.3 Hz, 4H).

Step 4: 1-Ethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]

Benzyl1-ethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate(530 mg, 1.3 mmol) was stirred in methanol (9.5 mL) with Pd/C (70 mg,0.070 mmol) under a balloon of hydrogen for 16 h. The reaction wasfiltered through a syringe filter and the solvent evaporated to give1-ethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (350 mg, 99%).ESI-MS m/z calc. 269.2. found 270.5 (M+1)⁺; Retention time: 0.80 minutes(3 min run).

9-Aza-1-methyl-1H-spiro[chromeno[4,3-e]pyrazole-4,4′-piperidine] Step 1:1-(3-Hydroxypyridin-2-yl)ethanone

A solution of MeMgBr (390 mL of 1.4 M in toluene/THF (75:25), 540 mmol)was heated at 60° C. and a solution of 3-hydroxypyridine-2-carboxylicacid (15 g, 110 mmol) and triethylamine (15 mL, 110 mmol) in THF (75 mL)was added dropwise over 3 hours. The resulting mixture was then stirredfor 2 hours at 60° C. The reaction mixture was cooled on an ice/brinebath and methyl formate (13 mL, 220 mmol) was added keeping the internaltemperature below 20° C. The reaction mixture was then acidified to pH5-6 with 1M aqueous HCl, and the layers were separated, and the aqueouslayer was extracted with ethyl acetate (3×). The organic phases werecombined, washed with brine, dried over sodium sulfate and evaporated todryness to afford 1-(3-hydroxypyridin-2-yl)ethanone (4.0 g, 27%). ESI-MSm/z calc. 137.1. found 138.3 (M+1)⁺; Retention time: 0.62 minutes (3 minrun).

Step 2: tert-Butyl4′-oxo-3′,4′-dihydrospiro[piperidine-4,2′-pyrano[3,2-b]pyridine]-1-carboxylate

A solution of 1-(3-hydroxy-2-pyridyl)ethanone (2.4 g, 18 mmol),tert-butyl 4-oxopiperidine-1-carboxylate (3.5 g, 18 mmol) andpyrrolidine (1.5 mL, 18 mmol) in MeOH (12 mL) was stirred at 80° C. for2 hours. After cooling to room temperature 1M aqueous HCl was addeduntil pH 4 was reached and the reaction mixture was stirred for further30 minutes. Methanol was evaporated, the remaining mixture was pouredinto water, and the pH adjusted to pH 7 with saturated aqueous sodiumcarbonate. The aqueous phase was extracted with ethyl acetate (3×),washed with brine (3×), dried over sodium sulfate and evaporated todryness. Purification by silica gel chromatography (50-100% ethylacetate in hexane) afforded tert-butyl4′-oxo-3′,4′-dihydrospiro[piperidine-4,2′-pyrano[3,2-b]pyridine]-1-carboxylate(2.2 g, 40%) as an orange oil that solidified upon standing. ESI-MS m/zcalc. 318.2. found 319.3 (M+1)⁺; Retention time: 1.16 minutes (3 minrun).

Step 3: tert-Butyl3′-(hydroxymethylene)-4′-oxo-3′,4′-dihydrospiro-[piperidine-4,2′-pyrano[3,2-b]pyridine]-1-carboxylate

To a suspension of sodium methoxide (594 mg, 11.0 mmol) in THF (5 mL)was added a suspension of tert-butyl4′-oxo-3′,4′-dihydrospiro[piperidine-4,2′-pyrano[3,2-b]pyridine]-1-carboxylate(1.0 g, 3.1 mmol) in THF (10 mL), followed by ethyl formate (2.5 mL, 31mmol) and the reaction mixture was stirred at 25° C. for 3 hours.Additional sodium methoxide (170 mg, 3.1 mmol) and ethyl formate (0.25mL, 3.1 mmol) were added and the reaction mixture was stirred at 25° C.for 1 hour. The reaction mixture was poured into water and was extractedwith ethyl acetate (4×). The aqueous layer was saturated with solid NaCland was extracted with ethyl acetate (5×). The organic layers werecombined and dried over sodium sulfate. The precipitate formed wasfiltered and washed with ether (2×). The solid product was dissolved inhot dichloromethane/MeOH (1:1) and filtered, and the filter cake wasrinsed with additional hot dichloromethane/MeOH (1:1) (4×) to dissolveall product and remove solid sodium sulfate. The combined filtrates wereevaporated to afford tert-butyl3′-(hydroxymethylene)-4′-oxo-3′,4′-dihydrospiro-[piperidine-4,2′-pyrano[3,2-b]pyridine]-1-carboxylate(560 mg, 52%) as a yellow solid. ESI-MS m/z calc. 346.2. found 347.5(M+I)⁺; Retention time: 0.98 minutes (3 min run).

Step 4: 9-Aza-1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]

tert-Butyl3′-(hydroxymethylene)-4′-oxo-3′,4′-dihydrospiro-[piperidine-4,2′-pyrano[3,2-b]pyridine]-1-carboxylate(160 mg, 0.46 mmol), tert-butyl N-amino-N-methyl-carbamate (68 mg, 0.46mmol) and HCl in dioxane (0.64 mL of 4.0 M, 2.5 mmol) in EtOH (1.6 mL)was heated at 50° C. for 3 hours. Another portion of HCl in dioxane(0.64 mL of 4.0 M, 2.5 mmol) was added and the reaction mixture wasstirred at 50° C. for 4 hours. The reaction mixture was poured intosaturated aqueous sodium carbonate and extracted with 10% MeOH indichloromethane (3×). The organic phases were combined, dried oversodium sulfate and concentrated to give9-aza-1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]. ESI-MSm/z calc. 256.1. found 257.3 (M+1)⁺; Retention time: 0.64 minutes (3 minrun).

2-Methylspiro[chromeno[3,4-d]thiazole-4,4′-piperidine]hydrochloric acidStep 1: (E)-tert-Butyl4-(hydroxyimino)spiro[chroman-2,4′-piperidine]-1′-carboxylate

tert-Butyl 4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (450 mg,1.41 mmol) and hydroxylamine 50 wt % in water (940 μL of 50% w/v, 14mmol) were combined in methanol (9.0 mL) and heated at reflux. After 24hours, the reaction mixture was diluted with ethyl acetate and waswashed with water. The organics were dried over MgSO₄, filtered andevaporated to dryness to yield (E)-tert-butyl4-(hydroxyimino)spiro[chroman-2,4′-piperidine]-1′-carboxylate (450 mg,98%). ESI-MS m/z calc. 332.4. found 333.3 (M+1)⁺; Retention time: 1.68minutes (3 min run).

Step 2: (E)-tert-Butyl4-(tosyloxyimino)spiro[chroman-2,4′-piperidine]-1′-carboxylate

A mixture of tert-butyl(4E)-4-hydroxyiminospiro[chromane-2,4′-piperidine]-1′-carboxylate (448mg, 1.34 mmol) and 4-methylbenzenesulfonyl chloride (514 mg, 2.70 mmol)were stirred in pyridine (2.1 mL) at 0° C. for 6 hours. The reactionmixture was poured over ice and the mixture was extracted with ethlyacetate. The organics were dried over sodium sulfate and evaporated togive (E)-tert-butyl4-(tosyloxyimino)spiro[chroman-2,4′-piperidine]-1′-carboxylate (532 mg,81%). ESI-MS m/z calc. 486.2. found 487.5 (M+1)⁺; Retention time: 2.20minutes (3 min run).

Step 3: tert-Butyl3-amino-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate

tert-Butyl(4E)-4-(p-tolylsulfonyloxyimino)spiro[chromane-2,4′-piperidine]-1′-carboxylate(3.36 g, 6.90 mmol) was dissolved in toluene (40 mL) and cooled in anice bath. Sodium ethoxide (2.5 mL of 21% w/v, 7.6 mmol) was addeddropwise and the reaction was allowed to warm to room temperatureovernight. The reaction was filtered through a pad of Celite. The celitewas washed with a 1N HCl solution and the two resulting layers wereseparated. The aqueous layer was neutralized with 4 M NaOH and wasextracted with ethyl acetate. The organics were dried over sodiumsulfate and evaporated to yield tert-butyl3-amino-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (33 mg, 1%).ESI-MS m/z calc. 332.4. found 333.7 (M+1)⁺; Retention time: 1.14 minutes(3 min run).

Step 4: 2-Methylspiro[chromeno[3,4-d]thiazole-4,4′-piperidine]

tert-Butyl 3-amino-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate(33 mg, 0.10 mmol), acetyl chloride (7.8 μL, 0.11 mmol), andN,N-diethylethanamine (28 μL, 0.20 mmol) were combined indichloromethane and stirred for 30 minutes. The reaction mixture wasdiluted with dichloromethane and was washed with 1N HCl, a saturatedsolution of NaHCO₃, and brine. The organics were dried over sodiumsulfate and evaporated to dryness. The residue was stirred in toluenewith Lawesson's reagent (40 mg, 0.10 mmol) at 70° C. overnight. Thereaction was diluted with dichloromethane and filtered through a pad ofCelite. The filtrate was evaporated and stirred with HCl in dioxane (1.0mL of 4.0 M, 4.0 mmol) for 1 h at room temperature. The reaction mixturewas evaporated to dryness to yield2-methylspiro[chromeno[3,4-d]thiazole-4,4′-piperidine] (27 mg, 20%).ESI-MS m/z calc. 272.4. found 273.1 (M+1)⁺; Retention time: 1.05 minutes(3 min run).

1H-spiro[chromeno[4,3-d]imidazole-4,4′-piperidine]

Benzyl 3-amino-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (600mg, 1.64 mmol) was added portion-wise to formamide (3.0 mL, 75 mmol) andthe mixture was heated at 180° C. for 2 h. After cooling to roomtemperature, 3 mL of 1 N NaOH was added and the resulting solution wasextracted with dichloromethane. The organics were combined and washedwith brine, dried over sodium sulfate, and evaporated to dryness. Thecrude material was filtered through silica gel eluting with 0-10%methanol in dichloromethane. The combined fractions were evaporated, andthe residue (400 mg) was dissolved in methanol (5 mL). Pd/C (210 mg,0.20 mmol) was added and the mixture was stirred under a balloon ofhydrogen. The reaction was filtered and the filtrate evaporated to give1H-spiro[chromeno[4,3-d]imidazole-4,4′-piperidine]. ESI-MS m/z calc.241.3. found 242.5 (M+1)⁺; Retention time: 0.27 minutes (3 min run).

1-Methyl-1H-spiro[chromeno[4,3-b]pyrrole-4,4′-piperidine] Step 1:2-(1-Methyl-1H-pyrrol-2-yl)phenol

1-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole (5.0 g,24 mmol), tetrakis(triphenylphosphine)palladium (0) (1.4 g, 1.2 mmol),2-bromophenol (4.2 g, 24 mmol), and potassium carbonate (24 mL of 2.0 M,48 mmol) were combined in 1,2-dichloroethane (291 mL). The mixture washeated at 80° C. for 16 h. The mixture was cooled to 25° C. before itwas partitioned between ethyl acetate and water. The layers wereseparated and the organic layer was washed with brine, dried overNa₂SO₄, and concentrated. Column chromatography (0-100% ethylacetate/hexanes) on the residue gave 2-(1-methylpyrrol-2-yl)phenol (1.4g, 34%). ESI-MS m/z calc. 173.2. found 174.2 (M+1)⁺; Retention time:1.76 minutes (3 min run).

Step 2: 1-Methyl-1H-spiro[chromeno[4,3-b]pyrrole-4,4′-piperidine]

A mixture of 2-(1-methylpyrrol-2-yl)phenol (1.20 g, 6.90 mmol),tert-butyl 4-oxopiperidine-1-carboxylate (1.38 g, 6.93 mmol),4-methylbenzenesulfonic acid hydrate (264 mg, 1.39 mmol), anddichloroethane (24 mL) was heated at 80° C. for 2 h. To the mixture wasadded HCl (1.7 mL of 4.0 M, 6.9 mmol) and the mixture was allowed tostrir at 50° C. for 1 h. The mixture was cooled to 25° C. and wasconcentrated in vacuo. The residue was taken up in dichloromethane andwas washed with saturated aqueous NaHCO₃. The organic layer was driedover sodium sulfate and concentrated. Column chromatography (0-100%ethyl acetate/hexanes) on the residue gave1-methyl-1H-spiro[chromeno[4,3-b]pyrrole-4,4′-piperidine]. ESI-MS m/zcalc. 254.3. found 255.2 (M+1)⁺; Retention time: 1.51 minutes (3 minrun).

Spiro[piperidine-4,4′-pyrazolo[1,5-d]pyrido[2,3-b][1,4]oxazine] Step 1:2-Chloro-3-(1H-pyrazol-1-yl)pyridine

A solution of 2-chloro-3-fluoro-pyridine (1.3 g, 10.0 mmol), 1H-pyrazole(749 mg, 11.0 mmol) and K₂CO₃ (4.1 g, 30.0 mmol) was stirred in DMF (15mL) at 80° C. for 16 hours. The reaction mixture was poured into waterand extracted with EtOAc (3×). The organics were combined, washed withwater (3×), brine, dried (Na₂SO₄) and evaporated to dryness.Purification by column chromatography (5 to 30% EtOAc in hexanes) gavethe desired product (0.7 g, 40%) as a white solid. ESI-MS m/z calc.179.3. found 180.3 (M+1)⁺. Retention time: 0.74 minutes (3 min run).

Step 2: tert-Butylspiro[piperidine-4,4′-pyrazolo[1,5-d]pyrido[2,3-b][1,4]oxazine]-1-carboxylate

To a solution of 2-chloro-3-pyrazol-1-yl-pyridine (338 mg, 1.88 mmol) inTHF (3.4 mL) at −78° C. was added butyllithium (979 μL of 2.5 M, 2.45mmol) dropwise over 5 minutes. The reaction mixture was then stirred atthe temperature for 15 minutes before the addition of tert-butyl4-oxopiperidine-1-carboxylate (562.5 mg, 2.82 mmol). The reaction wasallowed to come to 25° C., then heated at 70° C. for 4 hours. Thereaction mixture was poured into water, and extracted with EtOAc (3×).The organics were combined, washed with brine, dried (Na₂SO₄) andevaporated to dryness to yield a crude mixture that was purified bycolumn chromatography (5 to 30% EtOAC in hexanes) to give the titleproduct (35 mg, 5%) that was used in the next step without furtherpurification. ESI-MS m/z calc. 342.2. found 343.3 (M+1)⁺. Retentiontime: 1.46 minutes (3 min run).

Step 3:Spiro[piperidine-4,4′-pyrazolo[1,5-d]pyrido[2,3-b][1,4]oxazine]hydrochloride

To a solution of tert-butylspiro[piperidine-4,4′-pyrazolo[1,5-d]pyrido[2,3-b][1,4]oxazine]-1-carboxylate(35 mg, 0.10 mmol) in CH₂Cl₂ (1 mL) and MeOH (0.1 mL) was added HCl indioxane (256 μl of 4 M, 1.02 mmol) and the mixture was stirred at 40° C.for 4 hours. The reaction mixture was evaporated and the hydrochloricacid salt of the product was used without further purification. ESI-MSm/z calc. 242.1. found 243.5 (M+1)⁺. Retention time: 0.32 minutes (3 minrun).

Spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile]Step 1: tert-Butyl1-cyanospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate

To tert-butylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(54.6 g, 160.5 mmol) in THF (500 mL) at −75° C. was added chlorosulfonylisocyanate (17.5 mL, 200.6 mmol) in THF (100 mL) dropwise over a 30minutes period keeping the temperature below −70° C. and the mixture wasstirred at −75° C. for 1 hr. To this mixture was added DMF (37.3 mL,481.5 mmol) dropwise at −75° C. and the mixture was warmed to ambienttemperature, stirring for a total of 2 h. The mixture was quenched with1 L of 1N NaOH and transferred to a separatory funnel with 500 mL ofmethyl-tert-butyl ether. The aqueous phase was separated and extractedwith an additional 500 mL of methyl-tert-butyl ether. The combinedorganic phases were washed twice with 500 mL of brine, dried over MgSO₄,filtered and concentrated in vacuo to yield a crude mixture that waspurified by column chromatography with a 0-100% EtOAc/hexane gradient toyield tert-butyl1-cyanospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate(45 g, 76%) as an oil that crystallized upon standing. ESI-MS m/z calc.365.2. found 266.2 (M-Boc+1)⁺. Retention time: 2.43 minutes (3 min run).

Step 2: tert-Butyl1-cyanospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate

To a mixture of tert-butyl1′-cyanospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(27.0 g, 73.9 mmol) in DCM (200 mL) was added TFA (28.5 mL, 369 mmol).The mixture was stirred at room temperature for 3 h. The solvent wasremoved in vacuo and the mixture was diluted with 200 mL of MTBE andneutralized with 175 mL of 2N NaOH. The layers were separated and theaqueous phase was extracted with 200 mL of MTBE. The combined organicswere washed with brine and were dried over MgSO₄, filtered andconcentrated in vacuo. The residue solidified upon standing. The solidswere slurried with 100 mL of MTBE and 200 mL of hexane. The precipitatewas collected on a Buchner funnel to give tert-butyl1-cyanospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate.ESI-MS m/z calc. 265.1. found 266.2 (M+1)⁺. Retention time: 1.21 minutes(3 min run).7-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrileand7-fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrilewas also prepared using the procedures described above.

9-Methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] Step1: 3-Methyl-2-(1H-pyrrol-1-yl)phenol

A round bottom flask was charged with 2-amino-3-methyl-phenol (2.5 g,20.3 mmol) and acetic acid (37.5 mL) which provided a very darksolution. Stirring was commenced and the vessel was charged with2,5-dimethoxytetrahydrofuran (2.6 mL, 20.3 mmol) added neat dropwiseover a period of 2 minutes. The dark mixture was then heated at 100° C.for 3 h then 80° C. for 12 hours. The solvent was evaporated undervacuum and the crude residue purified by column chromatography using agradient of 0.5-50% EtOAc in hexanes to yield3-methyl-2-(1H-pyrrol-1-yl)phenol (2.9 g, 83%). ESI-MS m/z calc. 173.1.found 174.3 (M+1)⁺.Retention time: 1.31 minutes (3 min run).

Step 2:9-Methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]

To a solution of 3-methyl-2-(1H-pyrrol-1-yl)phenol (2.9 g, 16.6 mmol)and tert-butyl 4-oxopiperidine-1-carboxylate (3.6 g, 18.2 mmol) in drydichloromethane (57.4 mL) was added TFA (2.5 mL, 33.1 mmol) over a 15minutes period and the reaction was stirred at 25° C. for 12 hours.Another portion of TFA (2.5 mL, 33.1 mmol) was added at 25° C. and thereaction was stirred for 2 hours after which time a third portion of TFA(2.55 mL, 33.1 mmol) was added and the mixture was stirred at 25° C. foran additional 12 hours. The reaction Mixture was diluted with CH₂Cl₂(350 ml) and washed with 1M NaOH (50 ml). The organic phase was driedwith MgSO₄, filtered, evaporated to dryness and the resulting residuewas purified by silica gel chromatography eluting with 0.5-40% MeOH inCH₂Cl₂ to yield9-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (2.0g, 48%) obtained as a yellow oil. ESI-MS m/z calc. 254.1. found 255.3(M+1)⁺. Retention time: 1.08 minutes (3 min run).

8-Fluoro-1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochlorideStep 1: tert-Butyl6-fluoro-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (12.1 g, 60.9mmol) in pyrrolidine (7.3 mL, 87.2 mmol) and anhydrous methanol (16.5mL) was added 1-(5-fluoro-2-hydroxy-phenyl)ethanone (9.3 g, 60.7 mmol).The reaction mixture was stirred at 80° C. for 2.5 hours. The methanolwas removed under reduced pressure and the resulting residue wasdissolved in ethyl acetate (150 mL), washed with 1 N HCl (1×150 mL) andbrine (2×100 mL). The organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure to yield a yellow oil.The oil was diluted with hexanes (400 mL) and was heated at 60° C. untilin solution. Once dissolved, the solution was allowed to cool to 25° C.The crystals were collected via vacuum filtration, rinsed with hexanesto obtain tert-butyl6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (13.6 g,67%) as a light yellow solid. ESI-MS m/z calc. 335.2. found 336.7(M+1)⁺. Retention time 1.85 minutes (3 min run).

Step 2: tert-Butyl3-(diethoxymethyl)-6-fluoro-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate

To triethyl orthoformate (20.2 mL, 121.5 mmol) in dry dichloromethane(115 mL) under argon at −10° C. was added drop-wise BF₃.OEt₂ (15.4 mL,121.5 mmol). The solution was allowed to warm to 0° C. and was stirredfor 10 minutes. After, the solution was cooled to −78° C. prior to theslow drop-wise addition of tert-butyl6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (13.6 g,40.5 mmol) in dichloromethane (10 mL). iPr₂NEt (24.7 mL, 141.7 mmol) wasadded drop-wise over 30 minutes, and the mixture was slowly warmed toroom temperature and was stirred at 25° C. for 2 hours. The reactionmixture was diluted with the addition of dichloromethane (200 mL)followed by saturated aqueous sodium bicarbonate solution (200 mL). Themixture was shaken in a separatory funnel and separated. The organiclayer was washed with additional sodium bicarbonate solution (200 mL)and brine (200 mL). The organic layer was dried over sodium sulfate,filtered and concentrated to yield a residue that was purified by silicagel column chromatography (0-25% EtOAc/hexanes gradient) to givetert-butyl3-(diethoxymethyl)-6-fluoro-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate(3.9 g, 22%). ESI-MS m/z calc. 437.2. found 438.7 (M+1)⁺. Retention time2.14 minutes (3 min run).

Step 3:8-Fluoro-1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride

To a solution of tert-butyl3-(diethoxymethyl)-6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-P-carboxylate(2.6 g, 6.0 mmol) in ethanol (20 mL) was added hydrochloric acid (22.5mL of 4 M, 89.8 mmol) (4 M in dioxane). The reaction mixture was allowedto stir at 25° C. for 2 hours. The solvent was removed under vacuum, andthe obtained solid was azeotroped with ethanol (3×30 mL). The resultingbeige-white solid was fully dissolved in ethanol (21 mL) at 25° C. priorto the addition of tert-butyl N-amino-N-methyl-carbamate (1.1 mL, 7.2mmol). The solution was allowed to stir overnight. To the thickbeige-white slurry that formed was added hydrochloric acid (7.5 mL of 4M, 29.9 mmol) (4 M in dioxane). The mixture was heated at 60° C. toyield a clear yellow solution. After 1 hour at 60° C., a white thickslurry developed. The slurry was allowed to slowly cool to 25° C. over 4hours, and solids were collected by vacuum filtration. The cake wasrinsed with a 10% solution of ethanol in hexanes (2×). Residual solventswere further removed under reduced pressure providing8-fluoro-1-methyl-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride(1.9 g, 92%). ¹H NMR (400 MHz, DMSO) δ 7.59 (dd, J=9.3, 2.8 Hz, 1H),7.43 (s, 1H), 7.27-7.10 (m, 2H), 4.12 (s, 3H), 3.28-3.11 (m, 4H), 2.59(s, 1H), 2.22-2.02 (m, 414). ESI-MS m/z calc. 273.1. found 274.1 (M+1)+.Retention time 0.84 minutes (3 min run).

1-Ethyl-8-fluoro-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride

To a solution of tert-butyl3-(diethoxymethyl)-6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate(1.3 g, 3.0 mmol) in ethanol (10.4 mL) was added hydrochloric acid (11.1mL of 4 M, 44.6 mmol) (4 M in dioxane). The reaction mixture was allowedto stir at 25° C. for 2 hours. The solvent was removed under vacuum, andthe obtained solid was azeotroped with ethanol (3×30 mL). The resultingbeige-white solid was fully dissolved in ethanol (10.40 mL) at 25° C.prior to the addition of tert-butyl N-amino-N-ethyl-carbamate (571.2 mg,3.6 mmol). The solution was allowed to stir at 25° C. overnight. To thethick beige-white slurry that formed was added hydrochloric acid (3.7 mLof 4 M in dioxane, 14.9 mmol). The mixture was heated at 60° C. to yielda clear yellow solution. After 1 hour at 60° C., a thick white slurrydeveloped. The slurry was allowed to slowly, cool to 25° C. over 4hours, and solids were collected by vacuum filtration. The cake wasrinsed with a 10% solution of EtOH in hexanes (2×). Residual solvent wasfurther removed under reduced pressure providing1-ethyl-8-fluoro-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride(880 mg, 82%). ESI-MS m/z calc. 287.1. found 288.1 (M+1)⁺. Retentiontime 0.79 minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 7.52 (dd, J=9.4,2.8 Hz, 1H), 7.47 (s, 1H), 7.26-7.13 (m, 2H), 5.24 (s, 1H), 4.47 (q,J=7.2 Hz, 2H), 3.30-3.12 (m, 4H), 2.18-2.01 (m, 4H), 1.37 (t, J=7.2 Hz,3H).

8-Fluoro-2-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride

To tert-butyl3-(diethoxymethyl)-6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate(3.81 g, 8.71 mmol) was added hydrochloric acid (32.7 mL of 4.0 M indioxane, 130 mmol). The reaction mixture was allowed to stir at roomtemperature for 2 hours. The solvent was removed under vacuum, and theobtained solid was azeotroped with EtOH (lx 30 mL). The resulting solidwas suspended in EtOH (30.5 mL) and was treated with methylhydrazine(556 μL, 10.5 mmol) at 40° C. for 4 h. The mixture was then heated at80° C. for 1 h resulting in a yellow solution with an off whiteprecipitate. The solid was collected to give8-fluoro-2-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride(798 mg, 26%). ESI-MS m/z calc. 273.1. found 274.5 (M+1)⁺. Retentiontime 0.83 minutes (3 min run). Note: The yellow mother liquor wasevaporated to give a mixture of methyl regioisomers (1.71 g).

Spiro[benzo[b]imidazo[1,2-d][1,4]oxazine-4,4′-piperidine]dihydrochlorideStep 1: 1-(2-Fluorophenyl)-1H-imidazole

1,2-Difluorobenzene (25 mL, 254.0 mmol), imidazole (15.6 g, 228.6 mmol),and potassium carbonate (70.2 g, 508.0 mmol) were suspended in dimethylsulfoxide (15 mL). The reaction mixture was heated at 110° C. for 72hours. The reaction mixture was then partitioned between ethyl acetateand was water and washed several times with a saturated aqueous solutionof ammonium chloride to remove a small amount of di-imidazole material.The organic layer was then dried over sodium sulfate and evaporated todryness to yield 1-(2-fluorophenyl)imidazole (430 mg, 1%) that was usedwithout further purification. ESI-MS m/z calc. 162.1. found 163.3(M+1)⁺. Retention time 0.26 minutes (3 min run). ¹H NMR (400 MHz, DMSO)δ 8.04 (s, 1H), 7.69-7.62 (m, 1H), 7.57 (s, 1H), 7.54-7.45 (m, 2H),7.41-7.33 (m, 1H), 7.13 (s, 1H).

Step 2: tert-Butyl4-(1-(2-fluorophenyl)-1H-imidazol-2-yl)-4-hydroxypiperidine-1-carboxylate

1-(2-Fluorophenyl)imidazole (484 mg, 2.99 mmol) was dissolved in atetrahydrofuran (5 mL) under an atmosphere of argon. The reactionmixture was cooled to −78° C. n-Butyllithium (2.2 mL of 1.6 M, 3.58mmol) in hexanes was slowly added and the resulting mixture was stirredat −78° C. for 1 hour. tert-Butyl 4-oxopiperidine-1-carboxylate (892.2mg, 4.48 mmol) was then added as a solution in tetrahydrofuran (2 mL).The reaction mixture was allowed to slowly warm to room temperature andstir for 10 days. The crude material was evaporated to dryness and takento the next step without further purification. ESI-MS m/z calc. 361.2.found 362.1 (M+1)⁺. Retention time 1.12 minutes (3 min run).

Step 3: Spiro[benzo[b]imidazo[1,2-d][1,4]oxazine-4,4′-piperidine]

tert-Butyl4-[1-(2-fluorophenyl)imidazol-2-yl]-4-hydroxy-piperidine-1-carboxylate(294 mg, 0.81 mmol) and K₂CO₃ (337 mg, 2.44 mmol) were heated at 110° C.for 16 h in DMF (5 mL). The solvent was evaporated and the resultingmaterial was partitioned between dichloromethane and water. The organicswere separated and washed with brine, dried over sodium sulfate andevaporated. The crude material was purified by column chromatography(0-50% ethyl acetate in hexanes) to give tert-butylspiro[imidazo[2,1-c][1,4]benzoxazine-4,4′-piperidine]-1′-carboxylate(139 mg, 50%). ESI-MS m/z calc. 341.2. found 342.3 (M+1)⁺. Retentiontime 1.31 minutes (3 min run).

Step 4:Spiro[benzo[b]imidazo[1,2-d][1,4]oxazine-4,4′-piperidine]dihydrochloride

tert-Butylspiro[imidazo[2,1-c][1,4]benzoxazine-4,4′-piperidine]-1′-carboxylate(138 mg, 0.40 mmol) was stirred for 10 min in 4M HCl in dioxane (2 mL of4 M, 8.00 mmol). The reaction was evaporated to dryness to yield thespiro[benzo[b]imidazo[1,2-d][1,4]oxazine-4,4′-piperidine]dihydrochloride(97 mg, quantitative) that was used in next step without furtherpurification. ESI-MS m/z calc. 241.1. found 242.3 (M+1)⁺. Retention time0.40 minutes (3 min run).

7-Fluoro-1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochlorideStep 1: tert-Butyl7-fluoro-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (7.5 g, 37.8mmol) in pyrrolidine (4.5 mL, 54.1 mmol) and anhydrous methanol (10.2mL) was added 1-(4-fluoro-2-hydroxy-phenyl)ethanone (5.8 g, 37.6 mmol).The reaction mixture was stirred at 80° C. for 2.5 hours. The methanolwas removed under reduced pressure and the resulting residue wasdissolved in ethyl acetate (150 mL), washed with 1 N HCl (1×150 mL) andbrine (2×100 mL). The organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure to yield a yellow oil.The oil was diluted with hexanes (400 mL) and was heated at 60° C. untilin solution. Once dissolved, the solution was allowed to cool to 25° C.The crystals were collected via vacuum filtration, rinsing with hexanesto remove tert-butyl4-oxo-7-pyrrolidin-1-yl-spiro[chromane-2,4′-piperidine]-1′-carboxylate(8.6 g), which was collected as light yellow solid; ESI-MS m/z calc.386.2. found 387.2 (M+1)⁺; Retention time: 2.59 minutes (3 min run). Thefiltrate was concentrated and the residue was subjected to columnchromatography (0-100% ethyl acetate/hexanes) to give tert-butyl7-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (2.7 g,21%) as a light yellow solid; ESI-MS m/z calc. 335.2. found 336.2(M+1)⁺; Retention time: 2.49 minutes (3 min run). ¹H NMR (400 MHz,CDCl₃) δ 7.89 (dd, J=8.6, 6.7 Hz, 1H), 6.80-6.62 (m, 2H), 3.88 (d,J=12.1 Hz, 2H), 3.21 (t, J=12.0 Hz, 2H), 2.71 (s, 2H), 2.02 (d, J=12.8Hz, 2H), 1.62 (td, J=14.1, 4.8 Hz, 2H), 1.46 (s, 9H).

Step 2: (Z)-tert-Butyl3-(ethoxymethylene)-7-fluoro-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylateand tert-butyl3-(diethoxymethyl)-7-fluoro-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate

To

Triethyl orthoformate (4.0 mL, 24.1 mmol) in dry dichloromethane (23 mL)under argon at −10° was added dropwise BF₃.OEt₂ (3.1 mL, 24.2 mmol). Thesolution was allowed to warm to 0° C. and was stirred for 10 minutes.After, the solution was cooled to −78° C. prior to the slow drop-wiseaddition of tert-butyl7-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (2.7 g,8.0 mmol) in dichloromethane (1.2 mL). Diisopropylethylamine (4.9 mL,28.2 mmol) was added over 10 minutes, and the mixture was slowly warmedto 25° C. and was stirred at this temperature overnight. The reactionmixture was diluted with dichloromethane (500 mL) followed by saturatedaqueous sodium bicarbonate solution (500 mL). The mixture was shaken ina separatory funnel and separated. The organic layer was washed withsodium bicarbonate (500 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated. The residue was purified by silicagel column chromatography (0-25% EtOAc/hexanes) to provide a mixture often-butyl(3Z)-3-(ethoxymethylene)-7-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate(2.6 g, 82%) and tert-butyl3-(diethoxymethyl)-7-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate.ESI-MS m/z calc. 391.2. found 392.2 (M+1)⁺; Retention time: 2.69 minutes(3 min run).

Step 3:7-Fluoro-1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride

To tert-butyl(3Z)-3-(ethoxymethylene)-7-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate(2.6 g, 5.9 mmol) was added hydrochloric acid (22.3 mL, 89.1 mmol) (4 Min dioxane). The reaction mixture was allowed to stir at 25° C. for 2hours. Solvent was removed under vacuum, and the obtained solid wasdissolved in EtOH (3×25 mL) and the solvent was evaporated to dryness.The resulting beige-white solid was fully dissolved in ethanol (21 mL)at 25° C. prior to the addition of tert-butyl N-amino-N-methyl-carbamate(1.0 g, 7.1 mmol). The solution was allowed to stir at 25° C. overnight.To the thick beige-white slurry that formed was added hydrochloric acid,4 M in dioxane (7.4 mL, 29.7 mmol). The mixture was heated at 60° C. toyield a clear yellow solution. After 1″hour at 60° C., a thickbeige-white slurry developed. The slurry was allowed to slowly cool to25° C. over 1 hour, and solids were collected by vacuum filtration. Thecake was rinsed with a 10% solution of ethanol in hexanes (2×). Residualsolvent was further removed under reduced pressure providing7-fluoro-1-methyl-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride(1.4 g, 67%) as a light tan solid. ESI-MS m/z calc. 273.1. found 274.3(M+1)⁺; Retention time: 1.59 minutes (3 min run). ¹H NMR (400 MHz, MeOD)δ 7.80 (dd, J=8.7, 6.1 Hz, 1H), 7.45 (d, J=1.7 Hz, 1H), 7.00 (dd, J=9.8,2.6 Hz, 1H), 6.91 (td, J=8.6, 2.6 Hz, 1H), 4.14 (s, 3H), 3.53-3.42 (m,2H), 3.41-3.33 (m, 2H), 2.29 (d, J=13.9 Hz, 2H), 2.23-2.11 (m, 2H).

1-Isopropyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′ piperidine] Step 1:Benzyl1-isopropyl-1H-spiro[chromeno[4,3-e]pyrazole-4,4′-piperidine]-1′-carboxylate

A mixture of tert-butyl N-amino-N-isopropyl-carbamate (530.4 mg, 3.0mmol), (Z)-benzyl3-(hydroxymethylene)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate(1.10 g, 2.9 mmol) and TFA (223.4 μL, 2.9 mmol) in dichloromethane (10mL) was stirred 2 h. The reaction was concentrated to ⅓ volume, then TFA(˜1.5 mL) was added. The mixture was stirred for 30 min, thenconcentrated, neutralized with excess Et₃N, re-concentrated, andpurified by column chromatography (0-60% EtOAc/hexanes) to give benzyl1-isopropyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate(1.1 g, 91%) as a pale yellow oil. ESI-MS m/z calc. 417.2. found 418.3(M+I)⁺; Retention time: 2.07 minutes (3 min run).

Step 2: 1-Isopropyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]

Benzyl1-isopropylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate(1.1 g, 2.6 mmol) was stirred in methanol (14.4 mL) with Pd/C (140.3 mg,0.1318 mmol) under a balloon of hydrogen for 16 h. The reaction wasfiltered through a syringe filter and the solvent evaporated to give1-isopropylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (750 mg,100%). ESI-MS m/z calc. 283.2. found 284.3 (M+1)⁺; Retention time: 1.01minutes (3 min run).

7-Methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrileStep 1: tert-Butyl7-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate

To 5-methyl-2-pyrrol-1-yl-phenol (6.0 g, 33.6 mmol) in dichloromethane(75 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (6.61 g, 33.6mmol) then trifluoroacetic acid (3.1 mL, 40.3 mmol) and the mixture wasstirred at room temperature for 5.5 hours. The solvent was evaporatedand the crude residue was purified by column chromatography utilizing agradient of 0-100% dichloromethane in hexanes to yield tert-butyl7′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(7.1 g, 59%). ¹H NMR (400 MHz, CDCl₃) δ 7.22 (d, J=8.1 Hz, 1H),7.12-7.09 (m, 1H), 6.88 (s, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.29 (t, J=3.2Hz, 1H), 6:00-5.98 (m, 1H), 5.30 (s, 1H), 3.97 (s, 2H), 3.26 (t, J=12.2Hz, 2H), 2.32 (s, 3H), 2.09-2.01 (m, 2H), 1.87 (dt, J=13.3, 4.9 Hz, 2H),1.48 (s, 9H). ESI-MS m/z calc. 354.4. found 355.5 (M+1)+; Retention time2.28 minutes (3 min run).

Step 2: tert-Butyl1-cyano-7-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylateand7-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile

To tert-butyl7′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(5.0 g, 14.1 mmol) in THF (150 mL) at −78° C. was added dropwisechlorosulfonyl isocyanate (1.5 mL, 16.9 mmol) in THF (50 mL) over aperiod of 10 minutes. The mixture was stirred at that temperature for 4hours and then DMF (3.5 mL, 45.9 mmol) was added dropwise and themixture allowed to stir at room temperature overnight. The mixture wasconcentrated, diluted with DCM (500 mL) and washed with sat. NaHCO₃ (200mL), brine (200 mL), dried over MgSO₄ and evaporated to yield a cruderesidue that was purified by column chromatography (50-100%dichloromethane/hexane) to give tert-butyl1′-(methoxysulfonylcarbamoyl)-7′-methyl-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylateas a pale yellow oil (1.3 g, 24%). ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d,J=8.0 Hz, 1H), 6.98 (d, J=4.0 Hz, 1H), 6.96-6.88 (m, 2H), 6.05 (d, J=4.0Hz, 1H), 4.09-3.95 (m, 2H), 3.31-3.15 (m, 2H), 2.35 (s, 3H), 2.04 (d,J=14.0 Hz, 2H), 1.92-1.79 (m, 2H), 1.48 (s, 9H). ESI-MS m/z calc. 379.5.found 380.1 (M+1)⁺; Retention time 2.20 minutes (3 min run), and7-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile(0.5 g, 12%). ¹H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 7.88 (d, J=8.3 Hz,1H), 7.33 (d, J=4.1 Hz, 1H), 7.17 (s, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.42(d, J=4.1 Hz, 1H), 3.26-3.09 (m, 4H), 2.33 (s, 3H), 2.19-2.04 (m, 4H).ESI-MS m/z calc. 279.3. found 280.3 (M+1)⁺; Retention time 1.12 minutes(3 min run).

(1-Cyanospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-yl)methylacetate Step 1: tert-Butyl7-(bromomethyl)-1-cyanospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate

tert-Butyl1′-cyano-7′-methyl-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(200 mg, 0.527 mmol), 1-bromopyrrolidine-2,5-dione (93.8 mg, 0.527mmol), and 2-(1-cyano-1-methyl-ethyl)azo-2-methyl-propanenitrile (8.66mg, 0.0527 mmol) were combined in carbon tetrachloride (10 mL) and themixture was heated at 80° C. for 4 hours. The mixture was washed withwater, dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography (50-100%CH₂Cl₂/hexanes) to yield tert-butyl7′-(bromomethyl)-1′-cyano-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(115 mg, 47%). ESI-MS m/z calc. 457.1. found 458.5 (M+1)+; Retentiontime 2.43 minutes (3 min run).

Step 2:(1-Cyanospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-yl)methylacetate

tert-Butyl7′-(bromomethyl)-1′-cyano-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(33.0 mg, 0.0720 mmol) and potassium acetate (35.3 mg, 0.360 mmol) werecombined in DMF (0.5 mL) and the mixture was stirred at 80° C. for 18hours. The mixture was taken up in NH₄Cl (10 mL) and was extracted withCH₂Cl₂ (10 mL). Solvent was removed under reduced pressure and theresidue was purified by column chromatrograpy (0-10% EtOAc/CH₂Cl₂) toobtain tert-butyl7′-(acetoxymethyl)-1′-cyano-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(19.5 mg, 62%) as a clear oil. ESI-MS m/z calc. 437.2. found 438.5(M+1)+; Retention time 2.05 minutes (3 min run).tert-Butyl7′-(acetoxymethyl)-1′-cyano-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylatewas dissolved in CH₂Cl₂ (10 mL) before TFA (5.0 mL, 65 mmol) was added.The solvent was removed under reduced pressure to give(1′-cyanospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-yl)methylacetate (15 mg, 62%). ESI-MS m/z calc. 337.1. found 338.3 (M+1)⁺;Retention time 1.16 minutes (3 min run).

7-(Methoxymethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrileStep 1:7-Methyl-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo-[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile

To a solution of7′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile(250 mg, 0.895 mmol) in dichloromethane (5.0 mL) at 0° C. was addedtriethylamine (374 μL, 2.69 mmol) and (2,2,2-trifluoroacetyl)2,2,2-trifluoroacetate (124 μL, 0.895 mmol). The mixture was allowed towarm up to room temperature and was stirred overnight. The mixture wasconcentrated under reduced pressure and the residue was purified bycolumn chromatography (0-100% ethyl acetate/hexanes) to give7′-methyl-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile(250 mg, 74%) ESI-MS m/z calc. 375.3. found 376.3 (M+1)⁺; Retention time2.01 minutes (3 min run). ¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, J=8.8 Hz,1H), 6.99 (d, J=4.0 Hz, 1H), 6.96 (s, 1H), 6.94 (d, J=6.3 Hz, 1H), 6.07(d, J=4.0 Hz, 1H), 4.54-4.48 (m, 1H), 3.94 (d, J=14.2 Hz, 1H), 3.71-3.62(m, 1H), 3.34-3.25 (m, 1H), 2.36 (s, 3H), 2.20 (d, J=13.4 Hz, 2H),1.66-1.45 (m, 2H).

Step 2:7-(Bromomethyl)-F-(2,2,2-trifluoroacetyl)spiro[benzo-[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile

7′-Methyl-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile(250 mg, 0.666 mmol), 1-bromopyrrolidine-2,5-dione (119 mg, 0.666 mmol)and 2-(1-cyano-1-methyl-ethyl)azo-2-methyl-propanenitrile (10.9 mg,0.0666 mmol) were combined in carbon tetrachloride and the mixture washeated at 80° C. for 4 hours. The mixture was concentrated under reducedpressure and the residue was purified by column chromatography to give7′-(bromomethyl)-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile(53.2 mg, 18%).

Step 3:7-(Methoxymethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile

7′-(Bromomethyl)-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]-benzoxazine]-1′-carbonitrile(53.2 mg, 0.117 mmol) was treated with sodium methoxide (36 mg, 0.67mmol) at room temperature. The mixture was allowed to stir for 5 h atroom temperature before it was concentrated under reduced pressure. Theresidue was taken up in ethyl aceate, filtered, and concentrated to give7′-(methoxymethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile(9.0 mg, 4%). ESI-MS m/z calc. 309.2. found 310.3 (M+1)+; Retention time0.97 minutes (3 min run).

3-Methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrileStep 1:2,2,2-Trifluoro-1-(3-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)ethanone

To a solution of3′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (120 mg,0.41 mmol), and Et₃N (173 μL, 1.24 mmol) in dry dichloromethane (2.1 mL)at 0° C. under N₂, was added (2,2,2-trifluoroacetyl)2,2,2-trifluoroacetate (86 μL, 0.62 mmol) dropwise. After 5 min, thecooling bath was removed and the mixture was stirred for 3 h at 25° C.The solvent was removed under reduced pressure and the oily residue waspurified by silica-gel column chromatography eluting with 0.5-60% EtOAcin hexanes. The product2,2,2-trifluoro-1-(3′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl)ethanone(95 mg, 66%) was isolated as an off-white foamy solid. ESI-MS m/z calc.350.1. found 351.3 (M+1)+; Retention time 2.03 minutes (3 min run).

Step 2:3-Methyl-V-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde

POCl₃ (38 μL, 0.41 mmol) was added dropwise at 0° C. under N₂ to DMF (32μL, 0.41 mmol). The reaction was stirred for 30 min at this temperatureand a white solid formed, to which was slowly added a solution of2,2,2-trifluoro-1-(3′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl)ethanone(95 mg, 0.27 mmol) in dry DMF (0.7 mL). The reaction stirred for 4 h,poured onto ice, 0.8 ml of 1M NaOH was added and the product wasextracted with dichloromethane (3×5 mL). The organic phases werecombined, washed with brine, dried, filtered and concentrated and theresidue was purified by silica-gel column chromatography eluting with5-40% EtOAc in hexanes to yield3-methyl-F-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde(25 mg, 24%). ESI-MS m/z calc. 378.1. found 379.3 (M+1)⁺; Retention time1.83 minutes (3 min run).

Step 3:3-Methyl-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile

To a solution of3′-methyl-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbaldehyde(25 mg, 0.07 mmol) in ethanol (125 μL) at 60° C. was added an aqueoussolution of hydroxylamine hydrochloride (20.7 mg, 0.30 mmol) and sodiumacetate (41.2 mg, 0.50 mmol) in water (125.0 μL). The solution wasstirred at 60° C. for 2 hours. The reaction was cooled to 25° C., wateradded and the precipitate that formed was collected by filtration. Thesolids were washed thoroughly with water and dried under vacuum,dissolved in Ac₂O (119.1 μL, 1.26 mmol) and heated at 140° C. for 5 h.The reaction was cooled to 25° C., poured onto ice, basified by additionof solid NaHCO₃ until no more foaming occurred and extracted withdichloromethane (3×5 mL). The organic phases were combined, dried,filtered and concentrated to yield a residue that was purified by silicagel chromatography using a gradient of 0.5-45% EtOAc in hexanes to yield3-methyl-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile(10 mg, 40%). ESI-MS m/z calc. 375.1. found 376.3 (M+1)⁺; Retention time2.01 minutes (3 min run).

Step 4:3-Methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile

To a solution of3′-methyl-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile(10 mg, 0.027 mmol) in MeOH (159 μL) was added K₂CO₃ (7.7 mg, 0.056mmol) in one portion at 25° C. Water was added (35 mL), and the organicswere removed under vacuum and the aqueous layer was extracted withdichloromethane (3×100 ml). The organic phases were combined, dried,filtered, concentrated to a white solid, which was used directly in thenext step without further purification (7 mg, 93%).

9-Fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrileStep 1:9-Fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]

3-Fluoro-2-(1H-pyrrol-1-yl)phenol (2.7 g, 16.6 mmol) and tert-butyl4-oxopiperidine-1-carboxylate (3.3 g, 16.6 mmol) were dissolved in drydichloromethane (53.6 mL). TFA (2.3 mL, 30.3 mmol) was added over 15 minand stirring was continued for 12 hours. Additional TFA (2.3 mL, 30.3mmol) was added at 25° C. The reaction mixture was concentrated undervacuum and the residue diluted with dichloromethane (350 mL) then washedwith 1M NaOH (2×50 ml), dried, filtered and evaporated to dryness. Theresulting material was purified by silica gel chromatography elutingwith 0.5-40% MeOH in dichloromethane to yield9-fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (3.4g, 86%). ESI-MS m/z calc. 258.1. found 259.1 (M+1)⁺; Retention time 0.90minutes (3 min run).

Step 2:2,2,2-Trifluoro-1-(9-fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)ethanone

To a cold solution of9-fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (3.1g, 12.2 mmol) in dry dichloromethane (54 mL) under N₂ was successivelyadded Et₃N (5.1 mL, 36.6 mmol) and (2,2,2-trifluoroacetyl)2,2,2-trifluoroacetate (2.5 mL, 18.3 mmol). The cooling bath was removedand the mixture was stirred overnight at room temperature. The mixturewas concentrated, then purified by silica-gel column chromatographyeluting with 0.5-50% EtOAc in hexanes to yield2,2,2-trifluoro-1-(9-fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)ethanone(2.2 g, 50%) as a white foamy solid. ESI-MS m/z calc. 354.1. found 355.3(M+1)+; Retention time 2.11 minutes (3 min run).

Step 3:9-Fluoro-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde

POCl₃ (282 μL, 3.0 mmol) was added dropwise at 0° C. under N₂ to dry DMF(234 μL, 3.0 mmol). The reaction mixture was left for 20 min at thistemperature, which led to the formation of a white solid. A solution of2,2,2-trifluoro-1-(9′-fluorospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl)ethanone(715 mg, 2.0 mmol) dry DMF (5.4 mL) was added drop-wise and the coolingbath was removed. The reaction was poured over ice, 1M NaOH was added (5mL), then the pH was adjusted to 7 with 2M HCl. The mixture wasextracted with dichloromethane (3×10 mL). The organics were combined,dried with MgSO₄, filtered and evaporated to yield a residue that waspurified by silica-gel column chromatography eluting with 5-30% EtOAc inhexanes to yield9-fluoro-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde(770 mg, quant). ESI-MS m/z calc. 382.1. found 383.3 (M+1)+; Retentiontime 1.71 minutes (3 min run).

Step 4:9-Fluoro-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′piperidine]-1-carbonitrile

To a solution of9′-fluoro-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbaldehyde(715 mg, 1.9 mmol) in ethanol (3.5 mL) heated at 70° C. was added anaqueous solution of hydroxylamine hydrochloride (587 mg, 8.4 mmol) andsodium acetate (1.16 g, 14.20 mmol) in water (3.6 mL). The mixture washeated at 60° C. for 2 h. The mixture was cooled to 25° C., water addedand the precipitate formed was collected by filtration and washedthoroughly with water and dried under vacuum. The residue was dissolvedin Ac₂O (3.37 mL, 35.74 mmol) and heated at 140° C. for 5 h. Thereaction was cooled down to 25° C., poured onto ice, basified byaddition of NaHCO₃ (solid) until no more foaming occurred and wasextracted with dichloromethane (3×5 mL). The combined organic phaseswere dried, filtered and concentrated to yield a residue that waspurified by silica gel chromatography (gradient: 0.5-45% EtOAc inhexanes) to yield9-fluoro-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile(50 mg, 7%). ESI-MS m/z calc. 379.1. found 380.3 (M+1)+; Retention time1.82 minutes (3 min run).

Step 5:9-Fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile

To a solution of9′-fluoro-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile(170 mg, 0.45 mmol) dissolved in MeOH (2.7 mL) was added K₂CO₃ (130 mg,0.94 mmol) in one portion at rt. The reaction was monitored by LCMSuntil no starting material remained. Water was added (10 mL), and theorganic solvent removed under vacuum. The product was extracted withdichloromethane (3×30 mL), the organic phases were combined, dried withsodium sulfate, filtered, concentrated to a white solid, which was useddirectly in next step without further purification (104 mg, 82%). ESI-MSm/z calc. 283.1. found 284.1 (M+1)+; Retention time 0.94 minutes (3 minrun).

1-(Methylsulfonyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]Step 1: tert-Butyl1-(methylsulfonyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate]

To a solution of NCS (466 mg, 3.49 mmol) in dichloromethane (9.2 mL) at−10° C. was added dimethyl sulfide (393.9 μL, 5.38 mmol) dropwise andthe reaction mixture was stirred at this temperature for 10 min. Thesolution was cooled to −55° C. and a solution of tert-butylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (915mg, 2.69 mmol) in dichloromethane (5 mL) was added dropwise over 10 min.The cooling bath was removed and the mixture was stirred until thesolution reached 25° C. Water (10 ml) and EtOAc (40 ml) were added. Theorganic phase was separated, dried on sodium sulfate, filtered andconcentrated under reduced pressure to yield an orange oil (1.4 g) thatwas used in the next step without further purification. The orange oilyresidue obtained (1.4 g) was taken up in AcOH (5 mL) then H₂O₂ (671 μLof 30% w/v, 5.91 mmol) was added dropwise. After 15 min at 25° C.,another portion of H₂O₂ (671 μL of 30% w/v, 5.91 mmol) was addeddropwise and the reaction was monitored by HPLC until desapearance ofstarting materials. EtOAc (50 ml) and aqueous saturated NaHCO₃ (150 ml)were added and the product was carefully extracted (gas emission). Theorganic phase was washed with 150 mL of aq sat NaHCO₃, then with brine(50 ml). The organic phase was dried, filtered, concentrated underreduced pressure. Purification by silica-gel column chromatographyeluting with 5-100% EtOAc in hexanes yielded tert-butyl1′-methylsulfinylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(276 mg, 0.68 mmol) that was taken up in dry dichloromethane (1 mL).mCPBA (116.0 mg, 0.67 mmol) was added at 25° C. and the mixture wasstirred for 1 h. Another 30 mg of mCPBA was added and after 30 min,aqueous saturated NaHCO₃ (3 mL) was added and the product extractedtwice with dichloromethane (10 mL). The organic phases were combined,washed with brine, dried, filtered and concentrated to yield a residuethat was purified by silica-gel chromatography eluting with 5-100% EtOAcin hexanes. The desired product tert-butyl1′-methylsulfonylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(200 mg, 18% over 3 steps) was isolated as a yellow oil. ESI-MS m/zcalc. 418.2. found 419.5 (M+1)⁺; Retention time 1.93 minutes (3 minrun).

Step 2:1-(Methylsulfonyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]

To a solution of tert-butyl1′-methylsulfonylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(200 mg, 0.48 mmol) in dry dichloromethane (1 mL) at 0° C. was added TFA(147 μL, 1.91 mmol). The cooling bath was removed and the mixture wasstirred for 1.5 h at 25° C. The mixture was concentrated under reducedpressure and the residue obtained was taken up in dichloromethane (10ml) and was washed with aqueous saturated NaHCO₃ (5 ml). The aqueousphase was extracted twice with dichloromethane (2×10 ml) and the organicphases were combined, dried, filtered and concentrated to yield1′-methylsulfonylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]as a light yellow foamy solid (150 mg, 99%). ESI-MS m/z calc. 318.1.found 319.3 (M+1)+; Retention time 0.93 minutes (3 min run).1-(Methylsulfinyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]was also prepared using the procedure described above where only onealiquout of H₂O₂ was used in Step 1.

1-(Spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)ethanonehydrochloride Step 1: tert-Butyl1-bromospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate

To tert-butylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(13.2 g, 38.8 mmol) in CH₂Cl₂ (125 mL) at 0° C. was added NBS (7.25 g,40.7 mmol) in CH₂Cl₂ (25 mL) dropwise over 10 min. The mixture wasstirred at 0° C. for 5 min before it was diluted with 200 mL of 0.5MNa₂S₂O₃. The aqueous phase was removed and the organic phase was washedwith 200 mL of brine. The organic phase was separated, dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography (0-30% EtOAc/hexanes) to give tert-butyl1-bromospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate.ESI-MS m/z calc. 418.1. found 419.0 (M+1)+; Retention time: 2.29 minutes(3 min run).

Step 2: tert-Butyl1-acetylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate

To a solution of tert-butyl1′-bromospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(1.10 g, 2.60 mmol) and Pd₂(dba)₃OCHCl₃ (543 mg, 0.525 mmol) in1,4-dioxane (4.4 mL) was added tri-tert-butylphosphane (360 μL 1.31mmol), 1-vinyloxybutane (3.55 mL, 26.2 mmol) andN-cyclohexyl-N-methyl-cyclohexanamine (843 μL, 3.94 mmol). The mixturewas heated at 80° C. for 5 hours. The mixture was cooled to roomtemperature before 1N HCl (3 mL) was added and the mixture was stirredfor 1 hour. The mixture was poured into water and was extracted withethyl acetate (4×). The organics were combined, washed with water (2×),brine and evaporated. The residue was purified by column chromatography(0-20% ethyl acetate in hexanes) to give tert-butyl1′-acetylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(610 mg, 61%) as a yellow solid. ESI-MS m/z calc. 382.2. found 383.1(M+1)⁺; Retention time: 1.97 minutes (3 min run). ¹H NMR (400 MHz, DMSO)δ 7.52 (dd, J=8.1, 1.3 Hz, 1H), 7.35 (d, J=4.1 Hz, 1H), 7.24-7.12 (m,J=9.4, 8.0, 1.6 Hz, 2H), 7.08-6.98 (m, 1H), 6.35 (d, J=4.1 Hz, 1H), 3.88(d br, J=11.3 Hz, 2H), 3.13 (s br, 2H), 2.49 (s, 3H), 1.92-1.76 (m, 4H),1.41 (s, 9H).

Step 3:1-(Spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)ethanonehydrochloride

To a solution of tert-butyl1′-acetylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate(600 mg, 1.57 mmol) in CH₂Cl₂ (6 mL) was added HCl in Dioxane (3.9 mL of4 M, 15.7 mmol) and the mixture was stirred at room temperature for 1hour. The mixture was evaporated to dryness to give1-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-ylethanonehydrochloride (499 mg, 99%) which was used without further purification.ESI-MS m/z calc. 282.1. found 283.3 (M+1)⁺; Retention time: 0.86 minutes(3 min run).

4-(2-Methoxyethoxy)-3-methylbenzoic acid

To a solution of 4-hydroxy-3-methyl-benzoic acid (2.0 g, 13 mmol) in THF(24 mL) was added tetrabutylphosphonium hydroxide (18 mL of 40% w/v, 26mmol). The reaction mixture was cooled to 0° C. in an ice water bath andthen 1-bromo-2-methoxy-ethane (1.8 g, 1.2 mL, 13 mmol) was added. Thereaction mixture was then allowed to warm to room temperature and stirovernight. The reaction mixture was made acidic by addition of 1M HCland the reaction was extracted with ethyl acetate. The organics weredried over sodium sulfate and evaporated to yield 180 mg of4-(2-methoxyethoxy)-3-methylbenzoic acid (yield: 6%). ESI-MS m/z calc.210.2. found 209.2 (M-H)⁻. Retention time: 0.96 minutes (3 min run).The following compounds were synthesized using the procedures describedabove: 3-methyl-4-propoxybenzoic acid,4-(2-isopropoxyethoxy)-3-methylbenzoic acid, and4-(3-methoxypropoxy)-3-methylbenzoic acid.

3-Cyano-4-(2-methoxyethoxy)benzoic acid

3-Cyano-4-fluorobenzoic acid (500 mg, 3.03 mmol), 2-methoxyethanol (461mg, 6.06 mmol), and 60% w/w NaH (363 mg, 9.08 mmol) were combined inacetonitrile (15 mL) and the reaction mixture was heated at 70° C.overnight. The reaction mixture was made acidic by the addition of 1NHCl and was extracted with ethyl acetate. The organics were dried oversodium sulfate, evaporated and purified by column chromatography (0-10%methanol in dichloromethane) to yield 3-cyano-4-(2-methoxyethoxy)benzoicacid (625 mg, 93%). ¹H NMR (400 MHz, CD₃CN) δ 9.60 (s, 1H), 8.26 (d,J=1.9 Hz, 1H), 8.22 (dd, J=8.9, 2.2 Hz, 1H), 7.22 (d, J=8.9 Hz, 1H),4.34 (dd, J=5.2, 3.7 Hz, 2H), 3.79 (dd, J=5.2, 3.6 Hz, 2H), 3.41 (s,3H).The following compound was synthesized using the procedures describedabove: 3-cyano-4-propoxybenzoic acid.

3-Methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoic acid Step 1: Methyl3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoate

To sodium hydride (200 mg, 5.0 mmol) in DMF (6 mL) under N₂ was addedmethyl 4-hydroxy-3-methoxy-benzoate (920 mg, 5.0 mmol) and the mixturewas stirred for 10 min. 2-(Trifluoromethoxy)ethyltrifluoromethanesulfonate (prepared according to the procedure describedby Blazejewski, et. al. JOC, 2001, 66(3), 1061-1063) (1.2 g, 4.6 mmol)was then added dropwise and the solution was stirred at room temperaturefor 2 h, then at 50° C. for 2 h. The mixture was concentrated to asolid, and the residue was taken up in 50 mL of DCM before it was washedwith brine (20 mL), dried over MgSO₄ and purified by columnchromatography (0-25% EtOAc/hexane) to give methyl3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoate as a white solid.ESI-MS m/z calc. 294.1. found 295.3 (M+1)⁺; Retention time: 1.63 minutes(3 min run).

Step 2: 3-Methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoic acid

Methyl 3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoate (crude fromStep 1) was dissolved in THF (5 mL) and a suspension of LiOH (550 mg, 23mmol) in water (5 mL) was added. The mixture was stirred vigorously andheated at 60° C. for 6 h before it was concentrated to half volume.Water (5 mL) was added and the mixture was extracted with diethyl ether(1×10 mL). The aqueous layer was acidified with 4N HCl to pH 2. Theresulting mixture was extracted with ethyl acetate (3×10 mL) and thecombined organics were washed (1×10 mL H₂O, 1×10 mL brine), dried overMgSO₄ and evaporated to give3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoic acid (1.0 g, 82%) as awhite solid. ES1-MS m/z calc. 280.1. found 281.3 (M+1)⁺; Retention time:1.34 minutes (3 min run).

3-Methoxy-4-(2-(methylsulfonyl)ethoxy)benzoic acid Step 1: Methyl4-(2-bromoethoxy)-3-methoxybenzoate

To a solution of methyl 4-hydroxy-3-methoxy-benzoate (2.0 g, 11 mmol) inacetone (330 mL) was added K₂CO₃ (6.1 g, 44 mmol) followed by1,2-dibromoethane (6.2 g, 2.8 mL, 33 mmol). The mixture was stirred for2 d at 75° C. The mixture was cooled to ambient temperature and thesolids were removed by filtration. The filtrate was concentrated and theresidue was purified by column chromatograpy (10-25% ethylacetate/hexanes) to give methyl 4-(2-bromoethoxy)-3-methoxybenzoate.ESI-MS m/z calc. 288.0. found 289.1 (M+1)⁺; Retention time: 1.47 minutes(3 min run).

Step 2: Ethyl 3-methoxy-4-(2-(methylthio)ethoxy)benzoate

To a solution of methyl 4-(2-bromoethoxy)-3-methoxybenzoate (258 mg,0.892 mmol) in ethanol (2 mL) was added CH₃SNa (81.3 mg, 1.16 mmol). Thereaction mixture was stirred for 3 h at 90° C. before it was cooled tort and concentrated. Column chromatography (5-25% ethyl acetate/hexanes)gave ethyl 3-methoxy-4-(2-(methylthio)ethoxy)benzoate. ESI-MS m/z calc.270.1. found 271.5 (M+1)⁺; Retention time: 1.61 minutes (3 min run).

Step 3: Ethyl 3-methoxy-4-(2-(methylsulfonyl)ethoxy)benzoate

mCPBA (91 mg, 0.53 mmol) was added to a solution of ethyl3-methoxy-4-(2-(methylthio)ethoxy)benzoate (68 mg, 0.25 mmol) in DCM (3mL) at 0° C. The ice bath was removed, and the mixture was allowed tostir at ambient temperature for 2 h. To the mixture was added sat. aq.NaHCO₃ (2 mL) and DCM (3 mL). The layers were separated and the organiclayer was washed with sat. aq. NaHCO₃ (2 mL), dried over sodium sulfate,filtered, and concentrated. The residue was purified by columnchromatography (5-70% ethyl acetate/hexanes) to give ethyl3-methoxy-4-(2-(methylsulfonyl)ethoxy)benzoate. ESI-MS m/z calc. 302.1.found 303.5 (M+1)⁺; Retention time: 1.21 minutes (3 min run).

Step 4: 3-Methoxy-4-(2-(methylsulfonyl)ethoxy)benzoic acid

Ethyl 3-methoxy-4-(2-(methylsulfonyl)ethoxy)benzoate (30 mg, 0.099 mmol)was taken up in water (1.2 mL), H₂SO₄ (200 μL, 3.8 mmol), and AcOH (1300μL, 23 mmol). The mixture was heated at 90° C. for 6 h before it wascooled to ambient temperature and was concentrated under vacuum. Theresidue was purified by column chromatography (1-40% MeOH/DCM) to give3-methoxy-4-(2-(methylsulfonyl)ethoxy)benzoic acid. ESI-MS m/z calc.274.1. found 275.1 (M+1)⁺; Retention time: 0.69 minutes (3 min run).

3-Carbamoyl-4-isopropoxybenzoic acid

3-Cyano-4-isopropoxy-benzoic acid (50 mg, 0.24 mmol), hydrogen peroxide(280 μL of 30% w/v, 2.4 mmol), and 10% NaOH (240 μL of 10% w/v, 0.61mmol) were combined and stirred at room temperature for 16 h. Themixture was acidified with 4M HCl and was extracted with ethyl acetate(2×7 mL). The combined organics were washed with brine, dried oversodium sulfate and evaporated to give 3-carbamoyl-4-isopropoxy-benzoicacid (45 mg, 83%). ESI-MS m/z calc. 223.1. found 224.3 (M+1)⁺; Retentiontime: 1.49 minutes (4 min run).

4-tert-Butoxy-3-methoxybenzoic acid Step 1:4-tert-Butoxy-3-methoxybenzaldehyde

4-Hydroxy-3-methoxy-benzaldehyde (500 mg, 3.29 mmol), Boc₂O (1.74 g,7.97 mmol), and Sc(OTf)₃ (0.080 g, 0.16 mmol) were combined indichloromethane (5 mL). The reaction mixture was allowed to stir at roomtemperature for 24 h. Water (5 mL) and dichloromethane (5 mL) were addedand the two phases were separated. The aqueous layer was extracted withdichloromethane (3×5 mL) and the combined organics were stirred with 10%aqueous potassium hydroxide until all remaining starting material wasnot observed in the organic phase (TLC, 40% ethyl acetate in hexanes).The two phases were separated and the dichloromethane layer was thenwashed twice with a saturated aqueous solution of sodium chloride, driedover sodium sulfate, filtered, and evaporated to dryness to give4-tert-butoxy-3-methoxybenzaldehyde (130 mg, 19%) as a yellow oil.Rf=0.66 (SiO₂, 40% ethyl acetate in hexanes); ESI-MS m/z calc. 208.1.found 209.2 (M+1)⁺. Retention time: 0.96 minutes (6 min run).

Step 2: 4-tert-Butoxy-3-methoxybenzoic acid

4-tert-Butoxy-3-methoxybenzaldehyde (130 mg, 0.62 mmol) was suspended ina mixture of dioxane (520 μL) and potassium hydroxide (6.5 mL of 0.20 M,1.3 mmol). KMnO₄ (150 mg, 0.93 mmol) was added and the reaction wasstirred vigorously for 16 h. The reaction mixture was filtered and thenconcentrated to 3 mL. Hydrochloric acid (1M, 4 mL) was added and theresulting precipitate was filtered (after standing for 15 minutes) andwashed with 1M HCl and a small amount of water to yield4-tert-butoxy-3-methoxy-benzoic acid (68 mg, 49%) as a white solid.Rf=0.23 (SiO₂, 40% ethyl acetate in hexanes); ESI-MS m/z calc. 224.1.found 225.2 (M+1)⁺. Retention time: 1.66 minutes (3 min run). ¹H NMR(400 MHz, DMSO) 12.80 (s, 1H), 7.66-7.41 (m, 2H), 7.09 (d, J=8.8 Hz,1H), 3.78 (s, 3H), 1.32 (s, 9H).The following compounds were synthesized using the procedures describedabove: 4-tert-butoxy-3-methylbenzoic acid from4-hydroxy-3-methylbenzaldehyde, 2-fluoro-4,5-dimethoxybenzoic acid from2-fluoro-4,5-dimethoxybenzaldehyde, 4-tert-butoxy-2-methoxybenzoic acidfrom 4-hydroxy-2-methoxybenzaldehyde, 4-tert-butoxy-2-fluorobenzoic acidfrom 2-fluoro-4-hydroxybenzaldehyde, and 4-tert-butoxybenzoic acid from4-hydroxybenzaldehyde.

2-Fluoro-5-methoxy-4-(2-methoxyethoxy)benzoic acid Step 1:2-Fluoro-4-hydroxy-5-methoxybenzaldehyde

AlCl₃ (8.69 g, 65.2 mmol) was added to a solution of2-fluoro-4,5-dimethoxy-benzaldehyde (2.00 g, 10.9 mmol) in DCM (100 mL)under an atmosphere of argon. The reaction mixture was allowed to stirat room temperature for 16 h. The reaction mixture was slowly quenchedwith water. The layers were separated and the aqueous layer was thenextracted with ethyl acetate (3×). The combined organic layers weredried over sodium sulfate and then evaporated to dryness to yield2-fluoro-4-hydroxy-5-methoxy-benzaldehyde (1.82 g, 98%) as an off whitesolid. ESI-MS m/z calc. 170.0. found 171.0 (M+1)⁺. Retention time: 0.84minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 7.22 (d,J=6.7 Hz, 1H), 6.73 (d, J=11.9 Hz, 1H), 3.81 (s, 3H).

Step 2: 2-Fluoro-5-methoxy-4-(2-methoxyethoxy)benzaldehyde

2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde (0.500 g, 2.94 mmol) wasdissolved in DMF (2.6 mL) containing Cs₂CO₃ (2.88 g, 8.82 mmol).1-Bromo-2-methoxy-ethane (1.23 g, 828 μL, 8.82 mmol) was added and thereaction mixture was allowed to stir for 86 h. The reaction mixture wasfiltered and the filtrate was evaporated to dryness to give2-fluoro-5-methoxy-4-(2-methoxyethoxy)benzaldehyde. ESI-MS m/z calc.228.1. found 229.0 (M+1)⁺. Retention time: 1.14 minutes (3 min run).

Step 3: 2-Fluoro-5-methoxy-4-(2-methoxyethoxy)benzoic acid

2-Fluoro-5-methoxy-4-(2-methoxyethoxy)benzaldehyde (0.36 g, 1.6 mmol)was suspended in a mixture of dioxane (1.5 mL) and KOH (16 mL of 0.2 M,3.2 mmol). KMnO₄ (370 mg, 2.4 mmol) was added and the mixture wasstirred vigorously for 30 minutes. The reaction mixture was filtered andthe filtrate was concentrated to 10 mL (blue soln). HCl (4M, ˜2 mL) wasadded and the resulting precipitate was filtered and washed with 1M HCland then water (1 mL) to yield2-fluoro-5-methoxy-4-(2-methoxyethoxy)benzoic acid (300 mg, 78%) as awhite solid. ESI-MS m/z calc. 244.1. found 245.1 (M+1)⁺. Retention time:1.01 minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 12.96 (s, 1H), 7.30(d, J=7.0 Hz, 1H), 6.98 (d, J=12.5 Hz, 1H), 4.20-4.13 (m, 2H), 3.78 (s,3H), 3.71-3.63 (m, 2H), 3.31 (s, 3H).

4-tert-Butyl-3-cyanobenzoic acid Step 1: Methyl3-bromo-4-tert-butyl-benzoate

4-tert-Butylbenzoic acid (3.00 g, 16.8 mmol) was mixed with nitric acid(11 mL), water (8.4 mL), glacial acetic acid (51 mL), and bromine (2.9g, 19 mmol) in a two-neck flask containing an addition funnel and areflux condenser. An aqueous solution of silver nitrate (2.9 g, 17 mmol)in water (8.5 mL) was added dropwise over 30 minutes with vigorousstirring. The mixture was stirred at room temperature for 16 h before itwas poured into ice water. The solids were collected by vacuumfiltration. The solids were taken up in ethyl acetate and were washedwith water, then brine. The organic layer was dried over sodium sulfateand was concentrated in vacuo to give 3.2 g of a solid that was taken upin DMF (10 mL). To the solution was added potassium carbonate (4.7 g, 34mmol) and methyl iodide (4.8 g, 34 mmol). The mixture was concentratedto dryness and the residue was dissolved in dichloromethane and washedwith a 1N HCl solution, then brine. The organics were dried over sodiumsulfate and evaporated. The crude material was purified by columnchromatography (0-10% ethyl acetate in hexanes) to give methyl3-bromo-4-tert-butyl-benzoate (2.26 g, 25%). ¹H NMR (400 MHz, CD₃CN) δ8.19 (d, J=1.9 Hz, 1H), 7.91 (dd, J=8.3, 1.9 Hz, 1H), 7.65 (d, J=8.3 Hz,1H), 3.89 (s, 3H), 1.54 (s, 9H).

Step 2: Methyl 4-tert-butyl-3-cyanobenzoate

Methyl 3-bromo-4-tert-butyl-benzoate (2.26 g, 4.17 mmol) was dissolvedin dry DMF (2.1 mL) before CuCN (821 mg, 9.17 mmol) and NaCN (1.0 mg,0.021 mmol) were added. The mixture was flushed with nitrogen and wasstirred at 110° C. for 24 h. The reaction mixture was diluted with ethylacetate (70 mL) and was washed with water. The organics were dried oversodium sulfate and were evaporated to dryness. The crude material waspurified by column chromatography eluting with 0-10% ethyl acetate inhexanes to give methyl 4-tert-butyl-3-cyano-benzoate (390 mg, 43%).ESI-MS m/z calc. 217.1. found 218.5 (M+1)⁺; Retention time: 2.07 minutes(3 min run). ¹H NMR (400 MHz, CD₃CN) δ 8.31 (d, J=1.8 Hz, 1H), 8.16 (dd,J=8.4, 2.0 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 3.92 (s, 3H), 1.55 (s, 9H).

Step 3: 4-tert-Butyl-3-cyanobenzoic acid

A mixture of methyl 4-tert-butyl-3-cyano-benzoate (380 mg, 1.75 mmol),LiOH (3.5 mL of 2.0 M, 7.0 mmol) and 1,4-dioxane (3.5 mL) was heated at60° C. for 2 h. The reaction mixture was made acidic and was washed withdichloromethane (2×8 mL). The organics were combined, dried over sodiumsulfate and evaporated to dryness to give 4-tert-butyl-3-cyanobenzoicacid (348 mg, 98%). ¹H NMR (400 MHz, CD₃CN) δ 9.77 (s, 1H), 8.31 (d,J=1.8 Hz, 1H), 8.17 (dd, J=8.4, 1.9 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H),1.55 (s, 9H). 4-Cyano-3-methylbenzoic acid was also prepared using theprocedures described above.

(R)-3-Methoxy-4-(tetrahydrofuran-3-yloxy)benzoic acid Step 1: (R)-Methyl3-methoxy-4-(tetrahydrofuran-3-yloxy)benzoate

To a stirred solution of (3S)-tetrahydrofuran-3-ol (403 mg, 4.57 mmol),methyl 4-hydroxy-3-methoxy-benzoate (1.00 g, 5.49 mmol) andtriphenylphosphane (1.44 g, 1.27 mL, 5.49 mmol) in THF (13 mL) at 0° C.was added DIAD (1.11 g, 1.06 mL, 5.49 mmol). The ice bath was removedand the reaction mixture was stirred at room temperature for 16 h, thenat 55° C. for 4 h. The mixture was diluted with EtOAc and was washedwith sat. aq. NaHCO₃ (×2) and brine (×2). The organic layer was driedover Na₂SO₄, filtered and the solvent was evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel (0-30% ethyl acetate in hexane) to yield (R)-methyl3-methoxy-4-(tetrahydrofuran-3-yloxy)benzoate (0.97 g, 84%) as a viscousliquid. ESI-MS m/z calc. 252.1. found 253.3 (M+1)⁺; Retention time: 1.72minutes (3 min run).

Step 2: (R)-3-methoxy-4-(tetrahydrofuran-3-yloxy)benzoic acid

To (R)-methyl 3-methoxy-4-(tetrahydrofuran-3-yloxy)benzoate (0.95 g, 3.8mmol) were added dioxane (10 mL) and NaOH (10 mL, 1 M) and the mixturewas heated at 80° C. for 0.5 h. The solvent was evaporated under reducedpressure and the residue was dissolved in water and was washed withEtOAc (×3). The aqueous layer was acidified and a solid was formed. Theaqueous layer (with the solid) was washed with EtOAc (×3). The combinedorganics were dried over Na₂SO₄, filtered and the solvent was evaporatedunder reduced pressure to yield(R)-3-methoxy-4-(tetrahydrofuran-3-yloxy)benzoic acid (0.71 g, 79%) as awhite solid. ESI-MS m/z calc. 238.1. found 239.3 (M+1)⁺; Retention time:1.21 minutes (4 min run). ¹H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 7.54(dd, J=8.3, 1.4 Hz, 1H), 7.46 (d, J=1.3 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H),5.13-5.02 (m, 1H), 4.04-3.62 (m, 7H), 2.40-2.12 (m, 1H), 2.10-1.86 (m,1H).The following compounds were synthesized using the procedures describedabove: (R)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3-methoxybenzoicacid, (S)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3-methoxybenzoicacid, and 4-(3-hydroxycyclopentyloxy)-3-methoxybenzoic acid.

3-Methoxy-4-(2-methoxy-2-methylpropoxy)benzoic acid Step 1: Methyl3-methoxy-4-(2-methylallyloxy)benzoate

Methyl 3-methoxy-4-(2-methylallyloxy)benzoate was synthesized using theprocedure described above. ESI-MS m/z calc. 236.1. found 237.1 (M+1)⁺;Retention time: 1.63 minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 7.56(dd, J=8.4, 2.0 Hz, 1H), 7.47 (d, J=1.9 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H),5.07 (br s, 1H), 4.97 (br s, 1H), 4.55 (s, 2H), 3.83 (s, 3H), 3.82 (s,3H), 1.78 (s, 3H).

Step 2: Methyl 3-methoxy-4-(2-methoxy-2-methylpropoxy)benzoate

To methyl 3-methoxy-4-(2-methylallyloxy)benzoate (313 mg, 1.33 mmol) inMeOH (2.5 mL) was added H₂SO₄ (71 μL, 1.3 mmol) and the mixture washeated in a microwave vial at 100° C. for 15.5 h. The solvent wasevaporated under reduced pressure and the crude product was purified bycolumn chromatography on silica gel (0-30% ethyl acetate in hexane) toyield methyl 3-methoxy-4-(2-methoxy-2-methyl-propoxy)benzoate (208 mg,59%). ESI-MS m/z calc. 268.1. found 269.5 (M+1)⁺; Retention time: 1.46minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 7.57 (dd, J=8.4, 2.0 Hz,1H), 7.45 (d, J=1.9 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 3.90 (s, 2H), 3.83(s, 3H), 3.82 (s, 3H), 3.17 (s, 3H), 1.22 (s, 6H).

Step 3: 3-Methoxy-4-(2-methoxy-2-methylpropoxy)benzoic acid

Methyl 3-methoxy-4-(2-methoxy-2-methyl-propoxy)benzoate (177 mg, 0.660mmol), dioxane (1.9 mL) and NaOH (1.8 mL of 1.0 M, 1.8 mmol) werecombined and the mixture was heated at 80° C. for 15 min. The solventwas evaporated under reduced pressure and the crude mixture wasdissolved in water. The mixture was extracted with EtOAc (3×). Theaqueous layer was acidified with 1N HCl before it was extracted withEtOAc (3×). The combined organic layers were dried over Na₂SO₄, filteredand the solvent was evaporated under reduced pressure to yield3-methoxy-4-(2-methoxy-2-methyl-propoxy)benzoic acid (130 mg, 77%).ESI-MS m/z calc. 254.1. found 255.5 (M+1)⁺; Retention time: 1.14 minutes(3 min run). NMR (400 MHz, DMSO) δ 12.61 (s, 1H), 7.54 (dd, J=8.4, 1.9Hz, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 3.89 (s, 2H),3.81 (s, 3H), 3.17 (s, 3H), 1.22 (s, 6H).

4-((1R,2R)-2-Hydroxycyclopentyloxy)-3-methoxybenzoic acid Step 1: Methyl4-((1R,2R)-2-hydroxycyclopentyloxy)-3-methoxybenzoate

6-Oxabicyclo[3.1.0]hexane (2.43 g, 2.50 mL, 28.9 mmol) was addeddropwise to a stirred solution of methyl 4-hydroxy-3-methoxy-benzoate(5.26 g, 28.9 mmol) and BF₃.OEt₂ (410 mg, 369 μL, 2.89 mmol) in benzene(10 mL) at ambient temperature. The mixture was stirred at roomtemperature overnight before it was diluted with ethyl acetate and waswashed with 1N NaOH. The organic layer was dried over sodium sulfate,filtered and evaporated. The residue was purified by columnchromatography eluting with 0-100% EtOAc in hexanes to give methyl4-((1R,2R)-2-hydroxycyclopentyloxy)-3-methoxybenzoate. ESI-MS m/z calc.266.1. found 267.1 (M+1)⁺; Retention time: 1.16 minutes (3 min run).

Step 2: 4-((1R,2R)-2-Hydroxycyclopentyloxy)-3-methoxybenzoic acid

A solution of methyl4-[(1R,2R)-2-hydroxycyclopentoxy]-3-methoxy-benzoate (2.8 g, 11 mmol)and LiOH (21 mL of 2.0 M, 42 mmol) in dioxane (20 mL) was stirred at 50°C. overnight. The mixture was diluted with ethyl acetate and was washedwith water. The aqueous layer was acidified with 1N HCl and the productwas extracted into ethyl acetate. The organics were dried over sodiumsulfate, filtered and evaporated to give4-((1R,2R)-2-hydroxycyclopentyloxy)-3-methoxybenzoic acid. ESI-MS m/zcalc. 252.1. found 253.5 (M+1)⁺; Retention time: 1.07 minutes (3 minrun).

4-(2-Methoxyethoxy)-3-(trifluoromethyl)benzoic acid

3-Methoxypropan-1-ol (217 mg, 2.40 mmol),4-fluoro-3-(trifluoromethyl)benzoic acid (500 mg, 2.40 mmol), and NaH(240 mg, 6.0 mmol) were combined in THF (10 mL) and DMF (1 mL) at 0° C.under an atmosphere of nitrogen. The reaction mixture was stirred for 16h at room temperature. The reaction mixture was partitioned betweenethyl acetate and a 1M aqueous solution of hydrochloric acid. The layerswere separated and then the organic layer was washed with a saturatedaqueous solution of sodium chloride, dried over sodium sulfate, andevaporated to dryness. The crude material was purified by columnchromatography utilizing a gradient of 0-5% methanol in dichloromethaneto yield 4-(3-methoxypropoxy)-3-(trifluoromethyl)benzoic acid (213 mg,32%) as a white solid. ESI-MS m/z calc. 278.1. found 279.3 (M+1)⁺;Retention time: 1.38 minutes (3 min run).4-Propoxy-3-(trifluoromethyl)benzoic acid was prepared from4-fluoro-3-(trifluoromethyl)benzoic acid and3-fluoro-4-(2-methoxyethoxy)benzoic acid was prepared from3,4-difluorobenzoic acid using the procedure described above.

4-(2-Hydroxypropan-2-yl)-3-methoxybenzoic acid

4-Bromo-3-methoxy-benzoic acid (2.00 g, 8.67 mmol) was dissolved in THF(50 mL) and the solution was cooled to −78° C. n-BuLi in hexanes (7.6 mLof 2.5 M, 19 mmol) was added dropwise over 15 minutes. The reactionmixture was allowed to stir for 30 minutes at −78° C. and then acetone(640 μL, 8.9 mmol) was added in a dropwise manner. The reaction mixturewas allowed to stir for 30 minutes at −78° C., and then it was allowedto warm to room temperature. The reaction mixture was then diluted with100 mL of 1M aqueous sodium hydroxide. The organic layer was discardedand the aqueous layer was made acidic with 4M aqueous hydrochloric acid.The aqueous layer was then extracted 3 times with ethyl acetate. Thecombined extracts were dried over sodium sulfate and then evaporated todryness. The crude material was purified by column chromatographyutilizing a gradient of 0-5% methanol in dichloromethane to give4-(2-hydroxypropan-2-yl)-3-methoxybenzoic acid (618 mg, 34%). ESI-MS m/zcalc. 210.1. found 209.1 (M−1)⁻; Retention time: 0.68 minutes (3 minrun).

4-(3-Hydroxyoxetan-3-yl)-3-methoxybenzoic acid was also prepared usingthe method described above. ESI-MS m/z calc. 224.1. found 223 (M−1)⁻¹;Retention time: 0.69 minutes (3 min run).

1-(2-Methoxyethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid Step 1:Methyl 1-(2-methoxyethyl)-2-oxo-1,2-dihydropyridine-4-carboxylate andmethyl 2-(2-methoxyethoxy)isonicotinate

Methyl 2-oxo-1H-pyridine-4-carboxylate (2.00 g, 13.1 mmol), K₂CO₃ (3.61g, 26.1 mmol), THF (48 mL), DMF (38 mL) and 1-bromo-2-methoxy-ethane(3.63 g, 2.45 mL, 26.1 mmol) were combined and the mixture was stirredat 80° C. for 2 d. The reaction was filtered using ethyl acetate and thesolvent was evaporated under reduced pressure and the residue waspurified by column chromatography on silica gel (0-100% ethyl acetate inhexane) to yield methyl1-(2-methoxyethyl)-2-oxo-1,2-dihydropyridine-4-carboxylate [(1.22 g,44%), ESI-MS m/z calc. 211.1, found 212.3 (M+1)⁺; Retention time: 0.57minutes (3 min run); ¹H NMR (400 MHz, DMSO) δ 8.35 (d, J=5.2 Hz, 1H),7.41 (d, J=5.2 Hz, 1H), 7.21 (s, 1H), 4.47-4.36 (m, 2H), 3.89 (s, 3H),3.71-3.64 (m, 2H), 3.30 (s, 3H)] and methyl2-(2-methoxyethoxy)isonicotinate [(405 mg), ESI-MS m/z calc. 211.1.found 212.1 (M+1)⁺; Retention time: 1.04 minutes (3 min run); ¹H NMR(400 MHz, DMSO) δ 7.75 (d, J=7.0 Hz, 1H), 6.86 (s, 1H), 6.55 (d, J=7.0Hz, 1H), 4.09 (t, J=5.2 Hz, 2H), 3.85 (s, 3H), 3.58 (t, J=5.2 Hz, 2H),3.23 (s, 3H)].

Step 2: 1-(2-Methoxyethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid

Methyl 1-(2-methoxyethyl)-2-oxo-pyridine-4-carboxylate (1.56 g, 7.39mmol), dioxane (16 mL) and NaOH (20 mL of 1 M, 20 mmol) were combinedand the mixture was heated at 80° C. for 50 min. The solvent wasevaporated under reduced pressure and the residue was dissolved in waterbefore it was washed with EtOAc (3×). The aqueous layer was acidifiedwith 1N HCl and was washed with EtOAc (3×). The combined organic layerswere dried over Na₂SO₄, filtered and the solvent was evaporated underreduced pressure to yield 1-(2-methoxyethyl)-2-oxo-pyridine-4-carboxylicacid (1.0 g, 69%) as a white solid. ESI-MS m/z calc. 197.2. found 198.3(M+1)⁺; Retention time: 0.29 minutes (3 min run); ¹H NMR (400 MHz, DMSO)δ 13.59 (s, 1H), 7.72 (d, J=7.0 Hz, 1H), 6.84 (d, J=1.6 Hz, 1H), 6.53(dd, J=7.0, 1.6 Hz, 1H), 4.08 (t, J=5.2 Hz, 2H), 3.58 (t, J=5.2 Hz, 2H),3.23 (s, 3H).

2-(2-Methoxyethoxy)isonicotinic acid

Methyl 2-(2-methoxyethoxy)pyridine-4-carboxylate (562 mg, 2.66 mmol),dioxane (6 mL) and NaOH (7.1 mL of 1 M, 7.1 mmol) were combined and themixture was heated at 80° C. for 50 min. The solvent was evaporatedunder reduced pressure and the residue was dissolved in water before itwas washed with EtOAc (3×). The aqueous layer was acidified with 1N HCland was washed with EtOAc (3×). The combined organic layers were driedover Na₂SO₄, filtered and the solvent was evaporated under reducedpressure to yield 2-(2-methoxyethoxy)pyridine-4-carboxylic acid (457 mg,87%) as a white solid. ESI-MS m/z calc. 197.2. found 198.3 (M+1)⁺;Retention time: 0.66 minutes (3 min run); ¹H NMR (400 MHz, DMSO) δ 13.64(s, 1H), 8.32 (d, J=5.2 Hz, 1H), 7.39 (d, J=5.2 Hz, 1H), 7.18 (s, 1H),4.51-4.27 (m, 2H), 3.78-3.54 (m, 2H), 3.30 (s, 3H).

4-tert-Butyl-3-hydroxybenzoic acid

To a stirring solution of 4-tert-butyl-3-methoxy-benzoic acid (400 mg,1.92 mmol) in anhydrous DCM (9 mL) under N₂ at −78° C. was added BBr₃(5.76 mL of 1 M in DCM, 5.763 mmol) dropwise over 30 minutes. Themixture was allowed to stir at −78° C. for 1 hour, allowed to warm toroom temperature over 1 hour and then stirred at room temperature for 1hour. The mixture was poured onto crushed ice and was stirred for 10minutes. The organic layer was removed and the aqueous layer wasextracted with DCM (3×). The combined organics were combined, dried overNa₂SO₄ and then concentrated under reduced pressure to give4-tert-butyl-3-hydroxybenzoic acid. ESI-MS m/z calc. 194.1. found 195.1(M+1)⁺; Retention time: 1.45 minutes (3 min run); ¹H NMR (400 MHz, DMSO)δ 12.50 (s, 1H), 9.71 (s, 1H), 7.39 (d, J=1.1 Hz, 1H), 7.32 (dd, J=8.0Hz, 1.1 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 1.35 (s, 9H).

4-Ethyl-3-hydroxybenzoic acid Step 1: 4-Ethyl-3-methoxybenzoic acid

A mixture of 4-bromo-3-methoxy-benzoic acid (2.49 g, 10.9 mmol) andPd(dppf)Cl₂ (158 mg, 0.216 mmol) were stirred in dioxane (25 mL) andEt₂Zn (22 mL, 1 M in hexanes, 22 mmol) was added. The reaction mixturewas heated at 70° C. for 1 h. The mixture was cooled to room temperatureand was quenched with MeOH (1.1 mL). The solution was diluted with ethylacetate (20 mL) and was washed with 1 N HCl (10 mL). The combinedorganics were washed with brine, dried over sodium sulfate andevaporated to dryness to give 4-ethyl-3-methoxybenzoic acid. ESI-MS m/zcalc. 180.1. found 179.1 (M−1)⁻; Retention time: 1.77 minutes (3 minrun).

Step 2: 4-Ethyl-3-hydroxybenzoic acid

4-Ethyl-3-hydroxybenzoic acid was prepared using the method describedabove. ESI-MS m/z calc. 166.1. found 167.1 (M+1)⁺; Retention time: 1.09minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 12.62 (s, 1H), 9.64 (s,1H), 7.37 (d, J=1.5 Hz, 1H), 7.33 (dd, J=7.8, 1.5 Hz, 1H), 7.17 (d,J=7.8 Hz, 1H), 2.57 (q, J=7.5 Hz, 2H), 1.12 (t, J=7.5 Hz, 3H).4-Ethyl-3-methylbenzoic acid was also prepared using the proceduresdescribed above.

3-Methoxy-4-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoic acid Step 1:tert-Butyl 4-bromo-3-methoxybenzoate

MgSO₄ (4.82 g, 40.0 mmol), DCM (40 mL), and H₂SO₄ (533 μL, 10.0 mmol)were combined at 0° C. and the mixture was allowed to stir for 30minutes at 0° C. 4-Bromo-3-methoxy-benzoic acid (2.31 g, 10.0 mmol) and2-methylpropan-2-ol (4.78 mL, 50.0 mmol) were added and the mixture wasallowed to stir at rt overnight. The mixture was filtered to remove theMgSO₄ and the filtrate was washed with 1N NaOH. The layers wereseparated and the organic layer was dried over sodium sulfate and thesolvent was removed to yield 400 mg of tert-butyl4-bromo-3-methoxybenzoate. ESI-MS m/z calc. 286.0. found 287.0 (M+1)⁺;Retention time: 3.11 minutes (4 min run).

Step 2: tert-Butyl3-methoxy-4-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoate

To a microwave vial was added ZnF₂ (36 mg, 0.35 mmol) and Pd(tBu₃P)₂(7.2 mg, 0.014 mmol). The reaction vessel was purged with nitrogen for10 minutes before tert-butyl 4-bromo-3-methoxy-benzoate (200 mg, 0.70mmol) dissolved in DMF (2.5 mL) was added followed by(1-methoxy-2-methyl-prop-1-enoxy)-trimethyl-silane (180 mg, 1.1 mmol).The reaction vessel was placed in an 80° C. oil bath under an atmosphereof nitrogen and the mixture was allowed to stir overnight. The mixturewas allowed to cool to rt and was filtered through a frit and was washedwith brine and EtOAc. The organics were separated and dried over sodiumsulfate. The solvent was removed and the residue was taken on to thenext step without additional purification. ESI-MS m/z calc. 308.2. found309.4 (M+1)⁺; Retention time: 3.12 minutes (4 min run).

Step 3: 3-Methoxy-4-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoic acid

To the crude tert-butyl3-methoxy-4-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoate from Step 2was added DCM (1 mL) followed by TFA (540 μL, 7.0 mmol). The reactionwas allowed to stir for 2 h before it was concentrated in vacuo. Theresidue was dissolved in DMF, filtered and was purified by prep-HPLC(MeOH:H₂O, 1-99% in an HCl modifier) to give3-methoxy-4-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoic acid. ESI-MSm/z calc. 252.1. found 253.2 (M+1)⁺; Retention time: 2.45 minutes (4 minrun).

3-Fluoro-4-(oxetan-3-yloxy)benzoic acid Step 1: Methyl3-fluoro-4-(oxetan-3-yloxy)benzoate

NaH (80 mg, 2.0 mmol) was added to a mixture of oxetan-3-ol (150 mg, 2.0mmol) and DMF (2 mL) at 0° C. The reaction was allowed to stir for 10minutes before methyl 3,4-difluorobenzoate (170 mg, 1.0 mmol) was added.The reaction was then heated at 80° C. overnight. The reaction wasquenched with brine and was extracted with EtOAc (3×). The combinedorganic layers were dried over sodium sulfate and the solvent wasremoved to give methyl 3-fluoro-4-(oxetan-3-yloxy)benzoate. ESI-MS m/zcalc. 226.1. found 227.2 (M); Retention time: 2.36 minutes (4 min run).

Step 2: 3-Fluoro-4-(oxetan-3-yloxy)benzoic acid

Crude methyl 3-fluoro-4-(oxetan-3-yloxy)benzoate from Step 1, MeOH (1mL), and KOH (4.0 mL of 3.0 M, 12 mmol) were combined and the mixturewas allowed to stir for 3 h at rt. The mixture was extracted with EtOAcand the organic layer was discarded. The aqueous layer was then treatedwith 1N HCl and the pH was adjusted to pH 3. The aqueous layer wasextracted with EtOAc (3×) and the combined organic layers were driedover sodium sulfate and the solvent was removed. The crude acid was usedwithout further purification. ESI-MS m/z calc. 212.1. found 213.0(M+1)⁺; Retention time: 1.65 minutes (4 min run).

3-Formyl-4-isopropoxybenzoic acid Step 1: Methyl3-formyl-4-isopropoxybenzoate

To methyl 3-formyl-4-hydroxy-benzoate (10.0 g, 55.5 mmol), potassiumcarbonate (30.7 g, 222 mmol) and N,N-dimethylformamide (63 mL) was added2-iodopropane (11.1 mL, 111 mmol). The mixture was heated at 60° C. for18 hours. The mixture was filtered using ethyl acetate (200 mL) and thesolvent was evaporated under reduced pressure. The residue was dissolvedin ethyl acetate (150 mL) and was washed with water (3×75 mL) and asaturated aqueous solution of sodium chloride (1×75 mL). The organiclayer was dried over sodium sulfate, filtered and the solvent wasevaporated under reduced pressure to yield methyl3-formyl-4-isopropoxy-benzoate (98%) as a yellow viscous liquid. ESI-MSm/z calc. 222.2. found 223.3 (M+1)+; Retention time: 1.51 minutes (3 minrun). ¹H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.23 (d, J=2.3 Hz, 1H),8.17 (dd, J=8.8, 2.3 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H), 4.98-4.83 (m, 1H),3.85 (s, 3H), 1.38 (d, J=6.0 Hz, 6H).

Step 2: 3-Formyl-4-isopropoxybenzoic acid

To a solution of the ester (from previous step) in dioxane (4 mL) wasadded 2 mL of sodium hydroxide solution (5N). The reaction mixture washeated at 65° C. for 4 hours. The reaction mixture was cooled to roomtemperature and was diluted with 20 mL of water. The water layer wasextracted with 20 mL portion of ethyl acetate (2×). The organic extractswere discarded and the aqueous layer was made acidic with 1M HCl. Theresulting product was then extracted into ethyl acetate, dried overMgSO₄, filtered, and evaporated to dryness to yield3-formyl-4-isopropoxy-benzoic acid (320 mg, 55% over 2 steps) as a whitesolid. ¹H NMR (400 MHz, DMSO) δ 10.36 (s, 1H), 8.23 (d, J=2.5 Hz, 1H),8.15 (dd, J=2.5, 8.9 Hz, 1H), 7.37 (d, J=8.9 Hz, 1H), 4.96-4.87 (m, 1H),1.37 (d, J=5.6 Hz, 6H).

4-(2-Cyanopropan-2-yloxy)-3-methoxybenzoic acid

To oven dried (250 mL) 3-neck-flask with4-(cyanomethoxy)-3-methoxy-benzoic acid (1.0 g, 4.8 mmol) and anhydrousTHF (14 mL) cooled to −78° C. was added KHMDS in toluene (29 mL of 0.5M, 15 mmol) slowly. After 1 h, iodomethane (960 μL, 15 mmol) was addeddrop-wise and the mixture was stirred at −78° C. for 30 min. THF (14 mL)was added and the reaction was cooled to −78° C. KHMDS (19 mL of 0.5 M,9.5 mmol) was added. After 1 h, iodomethane was added (640 μL, 10 mmol)and the reaction was stirred for 30 min at −78° C. The reaction wasallowed to warm up to room temperature overnight. The reaction wasquenched with NH₄Cl. The aqueous layer was separated and was washed withethyl acetate (×3). The aqueous layer was acidified and was extractedwith ethyl acetate (×3). The organic layer was dried over Na₂SO₄ andfiltered. The solvent was evaporated under reduced pressure to yield amixture of mono and di-alkylated products as observed by LCMS (negativemode). ESI-MS m/z calc. 235.4. found 234.1 (M−1)⁻. Retention time: 0.93minutes (3 min run).

2-Cyano-4-isopropoxy-benzoic acid Step 1:2-Bromo-5-isopropoxybenzonitrile

2-Bromo-5-hydroxy-benzonitrile (20.0 g, 10.1 mmol) and K₂CO₃ (5.60 g,40.4 mmol) were taken-up in dry DMF (12.5 mL). 2-Iodopropane (2.00 mL,20.2 mmol) was added and the reaction mixture was heated at 60° C. for 2h. The mixture was diluted with ether (100 mL), filtered over celite andthe filtrate was washed with water (3×50 mL) and brine (50 mL), driedover MgSO₄, evaporated and purified by column chromatography (5-45%EtOAc/hexanes) to give 1.9 g (81%) of 2-bromo-5-isopropoxybenzonitrileas a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J=9.0 Hz, 1H),7.15 (d, J=2.9 Hz, 1H), 6.99 (dd, J=9.0, 3.0 Hz, 1H), 4.58-4.49 (m, 1H),1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 239.0. found 240.1 (M+1)⁺.Retention time: 1.81 minutes (3 min run).

Step 2: tert-Butyl 2-cyano-4-isopropoxybenzoate

2-Bromo-5-isopropoxybenzonitrile (200 mg, 0.83 mmol) in dry THF (0.5 mL)was added to a solution of butyllithium (570 μL of 1.6 M, 0.91 mmol) indry THF (0.5 mL) at −65° C. The mixture was stirred for 15 minutes andthen a solution of BOC anhydride (380 μL, 1.7 mmol) in dry THF (1 mL)was added and the reaction was stirred for an additional 15 min at thistemperature. The cooling bath was removed and water (2 mL) was added.The solvent was removed under vacuum and the mixture was extracted withdichloromethane (5 mL). The organic layer was dried, filtered andconcentrated to yield a brown oil that was purified on silica gelchromatography using a gradient of 5-70% ethyl acetate in hexanes togive tert-butyl 2-cyano-4-isopropoxybenzoate (82 mg, 38%). ESI-MS m/zcalc. 261.3. found 262.3 (M+1)⁺. Retention time: 1.96 minutes (3 minrun).

Step 3: 2-Cyano-4-isopropoxybenzoic acid

Trifluoroacetic acid (0.6 mL, 7.8 mmol) was added drop-wise to asolution of tert-butyl 2-cyano-4-isopropoxybenzoate (82 mg, 0.31 mmol)in dichloromethane (0.6 mL) at 0° C. under N₂ atmosphere. After theaddition was complete, the cooling bath was removed and stirring wascontinued for an additional 2 h at 25° C. The solvent was removed underreduced pressure to yield 2-cyano-4-isopropoxybenzoic acid that was useddirectly in the next step without further purification.

1-Methylindazole-7-carboxylic acid

Methyl 1-methylindazole-7-carboxylate (1 g, 5.3 mmol) was suspended in amixture of sodium hydroxide (12 mL of 1.0 M, 12 mmol) and 1,4-dioxane(8.7 mL). The reaction mixture was heated at 80° C. for 30 minutes. Thedioxane was evaporated off and the aqueous layer was extracted withethyl acetate three times and the extracts were discarded. The aqueouslayer was then acidified with 4M hydrochloric acid and then filtered andwashed with 1M hydrochloric acid to yield 1-methylindazole-7-carboxylicacid (0.9 g, 97%) as a white solid. ¹H NMR (400 MHz, DMSO) δ 13.31 (s,1H), 8.20 (s, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.87 (d, J=7.2 Hz, 1H), 7.21(t, J=7.6 Hz, 1H), 4.18 (s, 3H).

2,4-Diethoxy-3-methyl-benzoic acid

Methyl 2,4-dihydroxy-3-methyl-benzoate (193 mg, 1.06 mmol) was dissolvedin DMF (1 mL) containing cesium carbonate (1.03 g, 3.18 mmol).Iodoethane (847 μL, 10.6 mmol) was added and the reaction mixture wasallowed to stir for 86 hours. The reaction mixture was then filtered andevaporated to dryness. The crude material was then dissolved in amixture of dioxane (2 mL) and sodium hydroxide (1.1 mL of 1.0 M, 1.1mmol). The reaction mixture was then heated at 80° C. for 75 minutes.The dioxane was evaporated to dryness and the reaction mixture was madeacidic with 4M hydrochloric acid. The aqueous layer was extracted 3times with ethyl acetate. The combined ethyl acetate extracts were thendried over sodium sulfate, filtered, and evaporated to dryness to yield2,4-diethoxy-3-methyl-benzoic acid (189 mg, 80%) as a pale yellow solidwhich was used without further purification. ¹H NMR (400 MHz, DMSO) δ12.37 (s, 1H), 7.62 (d, J=8.7 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 4.08 (q,J=6.9 Hz, 2H), 3.87 (q, J=7.0 Hz, 2H), 2.06 (s, 3H), 1.36 (t, J=6.9 Hz,3H), 1.30 (t, J=7.0 Hz, 3H).

4-(Isopropylsulfonyl)-3-methylbenzoic acid Step 1:4-(Isopropylthio)-3-methylbenzoic acid

Butyllithium (16 mL of 1.6 M, 26 mmol) was added drop-wise to a mixtureof 4-bromo-3-methyl-benzoic acid (2.5 g, 12 mmol) and THF (63 mL) at−78° C. The mixture was allowed to stir at −78° C. for 30 minutes beforea solution of 2-isopropyldisulfanylpropane (1.7 g, 12 mmol) in THF (2mL) was added drop-wise. The mixture was allowed to stir at −78° C. for30 min, then 30 min at rt. The reaction mixture was then diluted with100 mL of 1M aqueous sodium hydroxide. The organic layer was discardedand the aqueous layer was made acidic with 4M aqueous hydrochloric acid.The aqueous layer was then extracted 3 times with ethyl acetate. Thecombined extracts were dried over sodium sulfate and then evaporated todryness. The crude material was purified by column chromatography usinga gradient of 0-5% MeOH in dichloromthane to give4-(isopropylthio)-3-methylbenzoic acid (870 mg, 18%). MS m/z calc.210.3. found 211.2 (M+1)⁺. Retention time: 2.32 minutes (3 min run).

Step 2: 4-(Isopropylsulfonyl)-3-methylbenzoic acid

3-Chlorobenzenecarboperoxoic acid (930 mg, 4.2 mmol) was added to amixture of 4-(isopropylthio)-3-methylbenzoic acid (250 mg, 1.2 mmol) anddichloromethane (5.0 mL) at 25° C. The mixture was allowed to stir at25° C. for 2 h before it was concentrated in vacuo. The white solidmaterial was taken up in dichloromethane and was subjected to columnchromatography (0-2% MeOH/dichloromethane) to give4-isopropylsulfonyl-3-methyl-benzoic acid (90 mg, 31%) as a white solid.ESI-MS m/z calc. 242.3. found 243.2 (M+1)⁺. Retention time: 1.57 minutes(3 min run). ¹H NMR (400 MHz, DMSO) δ 13.50 (s, 1H), 8.50-7.66 (m, 3H),3.50-3.47 (m, 1H), 2.67 (s, 3H), 1.19 (d, J=1.16 Hz, 6H).

3-Methyl-4-(trifluoromethoxy)benzoic acid

A mixture of 3-bromo-4-(trifluoromethoxy)benzoic acid (923 mg, 3.24mmol) and PdCl₂(dppf) (95 mg, 0.13 mmol) were stirred in 1,4-dioxane (9mL) in a three necked flask under argon atmosphere (a condensor wasadded to the flask). Dimethylzinc in toluene (3.2 mL of 2.0 M, 6.4 mmol)was added very slowly (caution: the reaction was very exothermic) andthe mixture was stirred at room temperature for 1 hour before it washeated at 70° C. for 18 h. The mixture was cooled to room temperaturebefore it was charged with additional dioxane (9 mL) and PdCl₂(dppf)(100 mg). The mixture was cooled to 0° C. before additional dimethylzinc in toluene (3.0 mL, 2.0M) was added. The ice bath was removed andthe mixture was heated at 70° C. overnight. The mixture was cooled toroom temperature and was quenched with methanol (2 mL) very slowly. Thesolution was diluted with ethyl acetate and was washed with 1N HCl (3×).The organic layer was washed with brine, dried over sodium sulfate andevaporated to dryness to yield 3-methyl-4-(trifluoromethoxy)benzoic acid(56%).

4-Methoxy-3,5-dimethyl-benzoic acid Step 1: Methyl4-hydroxy-3,5-dimethyl-benzoate

K₂CO₃ (3.0 g, 21 mmol) followed by iodomethane (1.2 mL, 20 mmol) wereadded to a solution of 4-benzyloxy-3,5-dimethyl-benzoic acid (5.0 g, 20mmol) in DMF (100 mL) and the mixture was stirred at room temperaturefor 6 h. The solution was diluted with water and was acidified with 1%aq. HCl. The mixture was extracted with EtOAc (3×200 mL). The combinedorganics were washed with water (200 mL), dried over sodium sulfate,filtered, and concentrated. The residue was taken up in degassed2-propanol (100 mL). Pd/C (10%, 500 mg) was added and the mixture wasagain degassed and was backfilled with Ar. The mixture was introduced toan atmosphere of H₂ (balloon) and was stirred overnight. The solids wereremoved by filtration through Celite and the filtrate was concetrated invacuo to provide methyl 4-hydroxy-3,5-dimethyl-benzoate (91%) as a whitesolid. ¹H NMR (400 MHz, DMSO) δ 7.56 (s, 2H), 3.76 (s, 3H), 3.38 (s,9H), 2.19 (s, 6H).

Step 2: 4-Methoxy-3,5-dimethyl-benzoic acid

Iodomethane (350 μL, 5.6 mmol) was added to a vigorously stirringsuspension of methyl 4-hydroxy-3,5-dimethyl-benzoate (0.50 g, 2.8 mmol)and K₂CO₃ (1.5 g, 11 mmol) in DMF (14 mL) and the mixture was stirredovernight at 60° C. The solution was cooled to room temperature and wasconcentrated in vacuo. The residue was taken up in water and mixture wasextracted with ethyl acetate (3×100 mL). The combined organics werewashed with water (300 mL) and dried over sodium sulfate, filtered andconcentrated to provide the intermediate ester. The residue was taken upin EtOH (20 mL) and NaOH (1.4 mL of 2.0 M, 2.8 mmol) was added. Thesolution was heated at 60° C. overnight. The solution was cooled to roomtemperature and the volatiles were removed in vacuo. The residue wastaken up in water and was extracted with EtOAc. The layers wereseparated and the organics were discarded. The aqueous layer wasacidified with 1N aq HCl, and was extracted with ethyl acetate (3×100mL). The combined organics were dried over sodium sulfate, filtered andconcentrated to provide 4-methoxy-3,5-dimethyl-benzoic acid (85%) as awhite solid.(4-Isopropoxy-3,5-dimethylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanonewas also prepared using the procedures described above.

1-Methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid

To 2-oxo-1H-pyridine-3-carboxylic acid (2.00 g, 14.4 mmol) in methanol(20 mL) was added a solution of KOH (1.60 g, 28.5 mmol) in water (3 mL)and the mixture was vigorously stirred until a thick suspension formed.Iodomethane (10 μL, 0.16 mmol) was added and the mixture was heated atreflux for 1.5 h. The mixture was concentrated to ⅓ volume and wasacidified to pH 1 with 6N HCl. The solids were filtered off and werewashed with water (3×2 mL) and acetonitrile (2×2 mL), and then dried invacuo to give 1-methyl-2-oxo-pyridine-3-carboxylic acid as a whitesolid. ESI-MS m/z calc 153.0. found 154.1 (M−1)⁻. Retention time: 0.65minutes (3 min run). 1-Ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acidwas also synthesized using the procedure described above.

1-Isopropyl-2-oxo-pyridine-4-carboxylic acid Step 1: Methyl1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate

To methyl 2-oxo-1H-pyridine-4-carboxylate (700 mg, 4.57 mmol) in dry DMF(4.4 mL) was added finely ground K₂CO₃ (2.53 g, 18.3 mmol) followed by2-iodopropane (914 μL, 9.14 mmol). The mixture was heated at 60° C.(external) for 1 h. The mixture was diluted with acetonitrile (10 mL)and was filtered. The filtrate was evaporated onto Celite and waspurified by column chromatography (0-100% EtOAc/DCM) to give methyl1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate (230 mg). ESI-MS m/zcalc 195.1. found 196.3 (M−1)⁻. Retention time: 1.09 minutes (3 minrun).

Step 2: 1-Isopropyl-2-oxo-pyridine-4-carboxylic acid

To methyl 1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate (225 mg)was added NaOH (550 μL of 25% w/w, 4.3 mmol) and water (0.6 mL). Themixture was rapidly stirred and heated at 50° C. for 1 h. The mixturewas cooled, acidified to pH 2 with 6N aq. HCl and the solids collected,rinsing with water and ACN (2×). The solid was dried in vacuo to give1-isopropyl-2-oxo-pyridine-4-carboxylic acid as a white solid. ESI-MSm/z calc 181.2. found 182.3 (M−1)⁻. Retention time: 0.86 minutes (3 minrun).

3-Fluoro-4-isopropoxybenzoic acid Step 1: Methyl3-fluoro-4-isopropoxybenzoate

To methyl 3-fluoro-4-hydroxy-benzoate (2.00 g, 11.8 mmol) in DMF (12.5mL) was added K₂CO₃ (6.50 g, 47.0 mmol) followed by 2-iodopropane (2.35mL, 23.5 mmol). The mixture was heated at 60° C. for 1.5 h. The mixturewas filtered using EtOAc and the filtrate was evaporated under reducedpressure. The residue was dissolved in EtOAc and was washed with waterand brine. The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure to give methyl3-fluoro-4-isopropoxybenzoate. ESI-MS m/z calc 212.1. found 213.3(M+1)⁺. Retention time: 1.70 minutes (3 min run).

Step 2: 3-Fluoro-4-isopropoxybenzoic acid

Methyl 3-fluoro-4-isopropoxybenzoate (from step 1), 1,4-dioxane (31 mL),and NaOH (31 mL of 1.0 M, 31 mmol) were combined and the mixture washeated at 80° C. for 20 min. The solvent was evaporated under reducedpressure. The crude mixture was dissolved in water and was washed withEtOAc (3×). The combined organics were discarded. The aqueous layer wasacidified and was extracted with EtOAc (3×). The organic layer was driedover sodium sulfate, filtered and the concentrated under reducedpressure to yield 3-fluoro-4-isopropoxy-benzoic acid (1.25 g, 72%) as awhite solid. ESI-MS m/z calc 198.1. found 199.3 (M+1)⁺. Retention time:1.34 minutes (3 min run).

2-Fluoro-4-isopropoxybenzoic acid and 4-isopropoxy-3-methylbenzoic acidwere also prepared using the procedures described above.

4-(1-Hydroxypropan-2-yl)-3-methoxybenzoic acid Step 1: Benzyl4-bromo-3-methoxybenzoate

4-Bromo-3-methoxy-benzoic acid (1.50 g, 6.49 mmol), K₂CO₃ (2.69 g, 19.5mmol), and DMF (10 mL) were combined and the mixture was allowed to stirfor 10 minutes. Bromomethylbenzene (849 μL, 7.14 mmol) was addeddropwise and the mixture was allowed to stir at rt for 1 h. The reactionmixture was quenched with brine and was extracted with EtOAc (3×). Theorganic layers were dried over sodium sulfate, filter and concentrated.The residue was purified using silica gel chromatography (5%-70% EtOAcin hexanes) to provide benzyl 4-bromo-3-methoxybenzoate (91%). ESI-MSm/z calc 320.0. found 321.0/323.0 (M+1)⁺. Retention time: 3.24 minutes(4 min run).

Step 2: Benzyl3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Pd(dppf)Cl₂ (197 mg, 0.269 mmol), KOAc (1.06 g, 10.8 mmol), benzyl4-bromo-3-methoxy-benzoate (865 mg, 2.69 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.03 g, 4.04 mmol), and DMF (10 mL) were combined and heated overnightat 100° C. The reaction mixture was quenched with brine and wasextracted with EtOAc (3×). The combined organic layers were dried oversodium sulfate, filtered, and concentrated. The residue was purified bysilica gel chromatography (3%-80% EtOAc in hexanes) to give benzyl3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (34%).ESI-MS m/z calc 368.2. found 369.3 (M+1)⁺. Retention time: 2.09 minutes(3 min run).

Step 3: 4-(1-Hydroxypropan-2-yl)-3-methoxybenzoic acid

Dichloro-[dicyclohexyl(phenyl)phosphaniumyl]-tritert-butylphosphaniumyl-palladium(981 mg, 0.150 mmol) and 2-bromoallyloxymethylbenzene (341 mg, 1.50mmol) were dissolved in DMF (1 mL). A solution of benzyl3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.11g, 3.00 mmol) in DMF (3 mL) was added the mixture was heated at 90° C.for 3 h. The mixture was then filtered through Celite using ethylacetate. The filtrate was then washed with brine, dried over sodiumsulfate, filtered, and concentrated. The residue from step 1 was takenup in isopropanol (2 mL) and was added to 10% Pd/C (160 mg, 0.150 mmol).The vessel was purged with nitrogen and a balloon of hydrogen was addedand the reaction mixture was allowed to stir overnight. The reactionmixture was filtered through Celite and the filtrate was concentrated.The residue was partitioned between aqueous 2M Na₂CO₃ and ethyl acetate.The layers were seperated and the organic phase was discarded. To theaqueous phase was added 1M HCl until the solution was pH 3. The solutionwas then extracted with EtOAc (3×) and the combined organic layers weredried over sodium sulfate, filtered, and concentrated to provide4-(1-hydroxypropan-2-yl)-3-methoxybenzoic acid. ESI-MS m/z calc 210.1.found 211.1 (M+1)⁺. Retention time: 1.19 minutes (3 min run).

5-Isopropoxyquinoline-8-carboxylic acid Step 1: 5-Isopropoxyquinoline

To a mixture of quinolin-5-ol (2.00 g, 13.8 mmol) and K₂CO₃ (7.62 g,55.1 mmol) in DMF (20 mL) was added 2-iodopropane (2.76 mL, 27.6 mmol).The reaction mixture was heated at 80° C. overnight before it waspartitioned between EtOAc and water. The layers were separated and theaqueous layer was extracted with EtOAc (2×). The combined organic layerswere washed with brine, dried over MgSO₄ and concentrated to dryness.The crude material was purified by column chromatography (10-20%EtOAc-Hex) to provide 5-isopropoxyquinoline (91%) as a light yellow oil.ESI-MS m/z calc 187.1. found 188.3 (M+1)⁺. Retention time: 1.06 minutes(3 min run).

Step 2: 8-Bromo-5-isopropoxy-quinoline

To a solution of 5-isopropoxyquinoline (1.87 g, 10.0 mmol) inacetonitrile (100 mL) was added NBS (1.78 g, 10.0 mmol) at 0° C. Themixture was stirred at rt for 2 h before the solvent was removed. Theresidue was partitioned between EtOAc and H₂O. The layers were separatedand the organic layer was washed with brine, dried over MgSO₄, andconcentrated. The crude material was purified by column chromatography(0-10% EtOAc-Hex) to provide 8-bromo-5-isopropoxy-quinoline (92%) as alight brown solid. ESI-MS m/z calc 265.1. found 266.1 (M+1)⁺. Retentiontime: 1.44 minutes (3 min run).

Step 3: 5-Isopropoxyquinoline-8-carboxylic acid

To a solution of 8-bromo-5-isopropoxy-quinoline (133 mg, 0.500 mmol) inTHF (2 mL) was added nBuLi (310 μL of 1.6 M, 0.50 mmol) dropwise at −78°C. under Ar. The reaction mixture was stirred at −78° C. for 30 min.Carbon dioxide was bubbled through the solution for 10 min. The mixturewas quenched with sat. aq. NH₄Cl before it was extracted with EtOAc(2×). The aqueous layer was acidified with 6N HCl to pH ˜4 and wasextracted with EtOAc (3×). The combined organics were washed with brine,dried over MgSO₄, filtered, and concentrated to dryness to give5-isopropoxyquinoline-8-carboxylic acid. ESI-MS m/z calc 231.1. found232.1 (M+1)⁺. Retention time: 1.28 minutes (3 min run).

4-(1-Cyano-1-methyl-ethoxy)-2-methoxy-benzoic acid Step 1: Methyl4-hydroxy-2-methoxy-benzoate

Thionyl chloride (953 μL, 13.1 mmol) was added dropwise to a solution of4-hydroxy-2-methoxy-benzoic acid (733 mg, 4.36 mmol) in methanol (30 mL)at 0° C. The mixture was stirred at 50° C. overnight. The reactionmixture was concentrated and the residue was dissolved in water (40 mL).The solution was neutralized with saturated sodium bicarbonate solutionand the product was extracted into ethyl acetate. The organics weredried over sodium sulfate, filtered and evaporated to dryness to givemethyl 4-hydroxy-2-methoxy-benzoate (99%). ESI-MS m/z calc 182.1. found183.1 (M+1)⁺. Retention time: 0.73 minutes (3 min run).

Step 2: Methyl 4-(cyanomethoxy)-2-methoxy-benzoate

Methyl 4-hydroxy-2-methoxy-benzoate (0.790 g, 4.34 mmol),2-bromoacetonitrile (361 μL, 5.42 mmol), and potassium carbonate (900mg, 6.51 mmol) were combined in N,N-dimethylformamide (5 mL). Thereaction mixture was stirred at room temperature for 16 hours. Thereaction mixture was diluted with 50 mL of ethyl acetate and 25 mL ofwater. The layers were separated and the water layer was extracted with50 mL of ethyl acetate. The combined organic layers were washed with asaturated aqueous solution of sodium chloride (2×). The organic layerwas then dried over sodium sulfate, filtered, and evaporated to drynessto yield methyl 4-(cyanomethoxy)-2-methoxy-benzoate (99%) as a brownoil. ES1-MS m/z calc 221.1. found 222.1 (M+1)⁺. Retention time: 1.08minutes (3 min run).

Step 3: Methyl 4-(1-cyano-1-methyl-ethoxy)-2-methoxy-benzoate

Methyl 4-(cyanomethoxy)-2-methoxy-benzoate (960 mg, 4.34 mmol) wasdissolved in tetrahydrofuran (1 mL) and N,N-dimethylformamide (4 mL).Sodium hydride (521 mg, 13.0 mmol) was added and the reaction mixturewas allowed to stir for 5 min. Iodomethane (1.35 mL, 21.7 mmol) wasadded and the reaction mixture was allowed to stir for 10 min. Thereaction mixture was quenched with water and extracted with ethylacetate. The ethyl acetate was dried over sodium sulfate, filtered andevaporated to dryness. The crude material was then dissolved intetrahydrofuran (10 mL) and was cooled to −78° C. under an atmosphere ofargon. LDA (2.2 mL of 2.0 M, 4.4 mmol) was added and the reactionmixture was stirred at −78° C. for 45 minutes. Iodomethane (1.35 mL,21.7 mmol) was added and the reaction mixture was allowed to slowly warmto room temperature. The reaction mixture was evaporated to dryness, andthen partitioned between ethyl acetate and a saturated aqueous solutionof ammonium chloride. The organic layer was washed two times with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, filtered, and evaporated to dryness. The crude product was thenpurified on 40 g of silica gel utilizing a gradient of 0-30% ethylacetate in hexanes to give methyl4-(1-cyano-1-methyl-ethoxy)-2-methoxy-benzoate (31%). ESI-MS m/z calc249.1. found 250.3 (M+1)⁺. Retention time: 1.59 minutes (3 min run).

Step 4: 4-(1-Cyano-1-methyl-ethoxy)-2-methoxy-benzoic acid

Methyl 4-(1-cyano-1-methyl-ethoxy)-2-methoxy-benzoate (340 mg, 1.36mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL). Lithiumhydroxide (98 mg, 4.1 mmol) was added and reaction mixture was heated at65° C. for 1 hour. The crude material was diluted with 10 mL of waterand was extracted two times with ether. The ether extracts werediscarded and the aqueous layer was made acidic with 4M HCl. The productwas then extracted into ethyl acetate, dried over sodium sulfate,filtered, and evaporated to dryness to yield4-(1-cyano-1-methyl-ethoxy)-2-methoxy-benzoic acid (78%) as a paleyellow solid. ESI-MS m/z calc 235.1. found 236.1 (M+1)⁺. Retention time:1.29 minutes (3 min run).

4-Isopropylsulfinylbenzoic acid Step 1: Ethyl4-isopropylsulfanylbenzoate

A mixture of ethyl 4-fluorobenzoate (390 mg, 2.32 mmol) andisopropylsulfanylsodium (273 mg, 2.78 mmol) in DMF (2.5 mL) was heatedat 80° C. for 36 h. The reaction mixture was diluted with ethyl acetatebefore being washed with 1N NaOH and then brine. The organic layer wasdried over sodium sulfate and evaporated. The residue was purified bycolumn chromatography eluting with 50-100% ethyl acetate in hexanes togive ethyl 4-isopropylsulfanylbenzoate (350 mg).

Step 2: Ethyl 4-isopropylsulfinylbenzoate

A solution of ethyl 4-isopropylsulfanylbenzoate (350 mg, 1.6 mmol) andH₂O₂ (180 μL of 30% w/v, 1.6 mmol) in AcOH (2 mL) was stirred at ambienttemperature for 3 h. The mixture was poured into sat. aq. Na₂CO₃ and thepH was adjusted to 10 with solid Na₂CO₃. The mixture was extracted withEtOAc (3×). The organics were combined and washed with sat. aq. Na₂CO₃,water (2×), then brine. The organic layer was dried over magnesiumsulfate and was evaporated to dryness. The residue was purified bycolumn chromatography (20-50% EtOAc in hexanes) to give ethyl4-isopropylsulfinylbenzoate (65%). ESI-MS m/z calc. 240.1. found 241.3(M+1)⁺. Retention time: 1.16 minutes (3 min run).

Step 3: 4-Isopropylsulfinylbenzoic acid

To a stirred solution of ethyl 4-isopropylsulfinylbenzoate (245 mg, 1.02mmol) in EtOH (1 mL) at room temperature was added NaOH (300 μL of 5.0M, 1.50 mmol) dropwise and the mixture stirred for 30 min. The pH of themixture was adjusted to 2 with 1N HCl before it was evaporated todryness. The solids were taken up in water, filtered, washed with water(2×), and dessicated to give 4-isopropylsulfinylbenzoic acid (80%) as awhite solid. ¹H NMR (400 MHz, DMSO) δ 13.30 (s, 1H), 8.11 (d, J=8.2 Hz,2H), 7.73 (d, J=8.2 Hz, 2H), 3.07-2.97 (m, 1H), 1.22 (d, J=6.9 Hz, 3H),0.90 (d, J=6.7 Hz, 3H).

4-(tert-Butylsulfonyl)benzoic acid Step 1: 4-(tert-Butylthio)benzoicacid

Ethyl 4-fluorobenzoate (1.5 g, 8.9 mmol) and tert-butylsulfanylsodium(2.00 g, 17.8 mmol) were combined in N,N-dimethylformamide (10 mL). Thereaction mixture was heated at 80° C. for 2 hours. A large amount ofprecipitate formed and an additional 15 mL of N,N-dimethylformamide wasadded and the reaction mixture was stirred for an additional 20 hours at80° C. The reaction mixture was partitioned between ethyl acetate (100mL) and water (100 mL). The organic layer was discarded, and the waterlayer was made acidic with 4M hydrochloric acid. The water layer wasextracted two times with ethyl acetate. The combined extracts were driedover sodium sulfate, filtered, and evaporated to dryness to yield4-(tert-butylthio)benzoic acid as a colorless oil. ESI-MS m/z calc.210.3. found 211.1 (M+1)⁺. Retention time: 1.74 minutes (3 min run).

Step 2: 4-(tert-Butylsulfonyl)benzoic acid

4-(tert-Butylthio)benzoic acid (from Step 1) was dissolved in AcOH (10mL) and hydrogen peroxide (5.0 mL of 30% w/w, 52 mmol) was added to thereaction mixture. The resulting mixture was heated at 80° C. for 2hours. The reaction mixture was then allowed to cool to roomtemperature, and was diluted with 50 mL of water and 100 mL of ethylacetate. The layers were separated and the aqueous layer was extractedwith ethyl acetate. The combined ethyl acetate extracts were dried oversodium sulfate, filtered, and evaporated to dryness to yield a whitesolid. The white solid was then dissolved in dichloromethane and wasevaporated to dryness. The solid was then dried under vacuum for 16hours to give 4-tert-butylsulfonylbenzoic acid (2.2 g, 92%) as a whitesolid. ESI-MS m/z calc. 242.1. found 243.1 (M+1)⁺. Retention time: 1.15minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 8.18 (d, J=8.0 Hz, 2H),7.94 (d, J=7.6 Hz, 2H), 1.25 (s, 9H). 4-(Ethylsulfonyl)benzoic acid wasalso synthesized using the procedures described above.

4-(Isobutylsulfonyl)benzoic acid Step 1: Methyl 4-(isobutylthio)benzoate

K₂CO₃ (1.23 g, 8.92 mmol) was added to a mixture of methyl4-sulfanylbenzoate (1.00 g, 5.95 mmol), 1-bromo-2-methyl-propane (970μL, 8.92 mmol), and DMF (10 mL) at rt. The mixture was allowed to stirfor 4 h at rt before the solids were filtered off. The solids werewashed with ethyl acetate, and then were discarded. The combinedfiltrates were partitioned between ethyl acetate (100 mL) and water (100mL). The layers were separated and the organic layer was washed withbrine, dried over sodium sulfate, filtered and concentrated to givemethyl 4-(isobutylthio)benzoate (82%) as a clear oil. ESI-MS m/z calc.224.1. found 225.2 (M+1)⁺. Retention time: 1.59 minutes (3 min run).

Step 2: Methyl 4-(isobutylsulfonyl)benzoate

m-CPBA (3.59 g, 15.6 mmol) was added to a solution of methyl4-(isobutylsulfanyl)benzoate (1.00 g, 4.46 mmol) in CH₂Cl₂ (20 mL) atrt. The mixture was allowed to stir for 2 h before it was concentratedin vacuo. Column chromatography (0-100% ethyl acetate/hexanes) on theresidue gave methyl 4-(isobutylsulfonyl)benzoate. ESI-MS m/z calc.256.1. found 257.2 (M+1)+; Retention time: 1.96 minutes (3 min run). ¹HNMR (400 MHz, CDCl₃) δ 8.23 (d, J=8.4 Hz, 2H), 8.00 (d, J=8.3 Hz, 2H),3.98 (s, 3H), 3.02 (d, J=6.5 Hz, 2H), 2.25 (dp, J=13.3, 6.6 Hz, 1H),1.07 (d, J=6.7 Hz, 6H).

Step 3: 4-(Isobutylsulfonyl)benzoic acid

A mixture of methyl 4-isobutylsulfonylbenzoate (1.00 g, 3.90 mmol), NaOH(10 mL of 1.0 M, 10 mmol), and 1,4-dioxane (10 mL) was heated at 80° C.for 1.5 h. The mixture was cooled to rt before it was concentrated invacuo. The solid residue was taken up in water and was washed with ethylacetate which was discarded. The aqueous layer was acidified with 1N HCland was extracted with ethyl acetate (2×). The combined organics werewashed with brine, dried over sodium sulfate, and were concentrated invacuo. Column chromatography (0-100% ethyl acetate/hexanes) on theresidue gave 4-(isobutylsulfonyl)benzoic acid (98%). ESI-MS m/z calc.242.1. found 243.2 (M+1)+; Retention time: 1.73 minutes (3 min run). ¹HNMR (400 MHz, CDCl₃) δ 8.30 (d, J=8.3 Hz, 2H), 8.05 (d, J=8.3 Hz, 2H),3.03 (d, J=6.5 Hz, 2H), 2.27 (dt, J=13.3, 6.6 Hz, 1H), 1.08 (d, J=6.7Hz, 6H).

3-Ethoxy-2-fluorobenzoic acid Step 1: 1-Ethoxy-2-fluorobenzene

A mixture of 2-fluorophenol (8.6 g, 77 mmol), iodoethane (9.2 mL, 120mmol) and potassium carbonate (21 g, 150 mmol) (finely powdered) wasstirred in acetone (100 mL) at 50° C. overnight, then at roomtemperature for 24 h. The mixture was filtered over a pad of silica gel,and was rinsing with ether. The solution was carefully concentrated (dueto volatility of product), then microfiltered to give1-ethoxy-2-fluoro-benzene (92%) as a yellow oil. ¹H NMR (CDCl₃, 500MHz), δ 7.12-6.94 (m, 2H), 6.91-6.86 (m, 1H), 6.83-6.77 (m, 1H), 4.01(q, J=7.0 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H).

Step 2: 3-Ethoxy-2-fluorobenzoic acid

To 1-ethoxy-2-fluoro-benzene (1.0 g, 7.1 mmol) in THF (10 mL) at −78° C.was added dropwise butyllithium (4.5 mL of 1.6 M, 7.2 mmol) followed byN′-(2-dimethylaminoethyl)-N,N,N¹-trimethyl-ethane-1,2-diamine (1.2 g,7.2 mmol). The mixture was stirred for 3 h at −78° C. before it wastransferred quickly via large cannula to a mixture of crushed dry ice(freshly crushed under N₂) under ether. The mixture was warmed to RT,diluted with 30 mL of 2M HCl (aq.), extracted with ethyl acetate (2×30mL), washed with 10 mL brine, and dried over MgSO₄ to give3-ethoxy-2-fluorobenzoic acid (65%) as a white solid. ESI-MS m/z calc.184.1. found 185.1 (M+1)+; Retention time: 1.04 minutes (3 min run). ¹HNMR (400 MHz, DMSO) δ 7.42-7.30 (m, 2H), 7.20-7.16 (m, 1H), 4.12 (q,J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).

3-(Hydroxymethyl)-4-isopropoxy-benzoic acid Step 1: Methyl3-formyl-4-isopropoxy-benzoate

Methyl 3-formyl-4-isopropoxy-benzoate (180 mg, 0.81 mmol) was dissolvedin tetrahydrofuran (4.8 mL) and LiBH₄ (35 mg, 1.6 mmol) was added. Thereaction was stirred at room temperature for 30 minutes before it wasquenched with methanol (3 mL). The reaction was neutralized by theaddition of a saturated aqueous solution of sodium bicarbonate (3 mL)and was then extracted with ethyl acetate (3×10 mL). The combinedorganics were washed with a saturated aqueous solution of sodiumchloride (1×10 mL), dried over sodium sulfate, filtered and the solventwas evaporated under reduced pressure to yield methyl3-(hydroxymethyl)-4-isopropoxy-benzoate (99%) as a viscous liquid.ESI-MS m/z calc. 224.3. found 225.3 (M+1)+; Retention time: 1.26 minutes(3 min run). ¹H NMR (400 MHz, DMSO) δ 8.09 (s, 1H), 7.89 (d, J=8.6 Hz,1H), 7.13 (d, J=8.6 Hz, 1H), 5.25 (t, J=5.6 Hz, 1H), 4.86-4.68 (m, 1H),4.54 (d, J=5.6 Hz, 2H), 3.87 (s, 3H), 1.35 (d, J=6.0 Hz, 6H).

Step 2: 3-(Hydroxymethyl)-4-isopropoxy-benzoic acid

To methyl 3-(hydroxymethyl)-4-isopropoxy-benzoate (180 mg, 0.80 mmol)and 1,4-dioxane (1.895 mL) was added sodium hydroxide (2.1 mL of 1.0 M,2.1 mmol) and the mixture was heated at 80° C. for 50 minutes. Thesolvent was evaporated under reduced pressure. The crude mixture wasdissolved in water (10 mL) and was washed with ethyl acetate (3×10 mL)which was discarded. The aqueous layer was acidified with hydrochloricacid. The aqueous layer was extracted with ethyl aceatate (3×10 mL). Thecombined organics were dried over sodium sulfate, filtered and thesolvent was evaporated under reduced pressure to yield3-(hydroxymethyl)-4-isopropoxy-benzoic acid (89%) as a white solid.ESI-MS m/z calc. 210.2. found 211.3 (M+1)+; Retention time: 1.01 minutes(3 min run).

3-Methyl-4-methylsulfonyl-benzoic acid

Thionyl chloride (3.55 mL, 48.7 mmol) was added dropwise to a solutionof 4-fluoro-3-methyl-benzoic acid (2.50 g, 16.2 mmol) in methanol (102mL) at 0° C. The mixture was stirred at 50° C. for 2 hours. The reactionmixture ws evaporated to dryness and the crude ester was then dissolvedin N,N-dimethylformamide (10 mL). Sodium thiomethoxide (2.50 g, 35.7mmol) was added and the reaction mixture was heated at 80° C. for 15hours. The reaction mixture was then partitioned between 1M hydrochloricacid and ethyl acetate. The layers were separated and the organic layerwas washed with 1M hydrochloric acid. The ethyl acetate layer was thendried over sodium sulfate, filtered, and evaporated to dryness. Theresultant acid and ester mixture was suspended in acetic acid (20 mL).Hydrogen peroxide (5.0 mL of 30% w/w) was added and the reaction mixturewas heated at 80° C. for 2 hours. The reaction mixture was diluted withwater (20 mL) and the resulting mixture was extracted three times with50 mL portions of ethyl acetate. The combined organics were evaporatedto dryness and the residue was dissolved in tetrahydrofuran (10 mL).Water (10 mL) and lithium hydroxide (1.17 g, 48.7 mmol) were then addedand the reaction mixture was heated at 65° C. for 4 hours. The reactionmixture was diluted with water (20 mL) and the resulting mixture wasextracted three times with 20 mL portions of ethyl acetate. The aqueouslayer was then made acidic with aqueous 6M hydrochloric acid and wasextraced 3 times with 50 mL portions of ethyl acetate. The combinedethyl acetate extracts were dried over sodium sulfate, filtered, andevaporated to dryness to yield 3-methyl-4-methylsulfonyl-benzoic acid(2.25 g, 72%) as a white solid. ESI-MS m/z calc. 214.0. found 215.0(M+1)+; Retention time: 0.97 minutes (3 min run). ¹H NMR (400 MHz, DMSO)δ 13.48 (s, 1H), 8.07-7.94 (m, 3H), 3.27 (s, 3H), 2.70 (s, 3H).

4-Isopropoxy-2,5-dimethylbenzoic acid Step 1:1-Iodo-4-isopropoxy-2,5-dimethylbenzene

K₂CO₃ (1.23 g, 8.87 mmol) followed by 2-iodopropane (806 μL, 8.06 mmol)were added to a solution of 4-iodo-2,5-dimethyl-phenol (1.00 g, 4.03mmol) in DMF (40 mL) and the solution was heated at 50° C. for 24 h. Themixture was then acidified with 1% aq HCl before it was extracted withEtOAc (3×100 mL). The combined organics were washed with 1 N NaOH (3×200mL), dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by column chromatography (0-10% ethyl acetate/hexanes) toprovide 1-iodo-4-isopropoxy-2,5-dimethylbenzene (42%) as a yellow oil.

Step 2: 4-Isopropoxy-2,5-dimethylbenzoic acid

A solution of 1-iodo-4-isopropoxy-2,5-dimethylbenzene (450 mg, 1.6 mmol)in THF (7.8 mL) was cooled to −78° C. before nBuLi (620 mL, 2.5 M, 1.6mmol) was added dropwise. The mixture was allowed to warm to 0° C., thenit was cooled to −78° C. before it was added dropwise to a flaskcontaining crushed, dry CO₂. The mixture was allowed to warm to roomtemperature and was stirred overnight. The mixture was poured over iceand was acidified with 1N HCl. The mixture was extracted with ethylacetate (3×) and the combined organics were washed with brine, driedover sodium sulfate, and concentrated to give4-isopropoxy-2,5-dimethylbenzoic acid (67 mg, 10%). ESI-MS m/z calc.208.1. found 209.1 (M+1)+; Retention time: 1.55 minutes (3 min run).

Spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl(4-(2,2,2-trifluoroethoxy)phenyl)methanone

4-(2,2,2-Trifluoroethoxy)benzoic acid (22 mg, 0.10 mmol), HATU (42 mg,0.11 mmol), and DMF (0.8 mL) were combined and allowed to srit at roomtemperature for 10 minutes. The activated acid was then added tospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (28 mg, 0.10mmol) followed by the addition of Et₃N (84 μL, 0.60 mmol). The reactionmixture was stirred at room temperature for 17 h before it was filteredand purified by prep-HPLC (5 mM HCl/H₂O and MeOH) to providespiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl(4-(2,2,2-trifluoroethoxy)phenyl)methanone.ESI-MS m/z calc. 442.2. found 443.4 (M+1)⁺. Retention time: 2.05 minutes(4 min run).

(4-(Isopropylsulfonyl)-3-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-e]pyrazole-4,4′-piperidine]-1′-yl)methanone

Triethylamine (152 μL, 1.1 mmol) was added to a mixture of1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride(108 mg, 0.33 mmol), 4-(isopropylsulfonyl)-3-methylbenzoic acid (80 mg,0.33 mmol), HATU (126 mg, 0.33 mmol), and dichloromethane (2 mL) at 25°C. The mixture was heated at 40° C. for 3 h. The mixture wasconcentrated and the residue was purified by column chromatography(0-100% ethyl acetate/hexanes) to give(4-(isopropylsulfonyl)-3-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(107 mg, 65%) as a fluffy white solid. ESI-MS m/z calc. 479.6. found480.3 (M+1)⁺. Retention time: 2.24 minutes (3 min run).

9-Aza-(4-isopropoxy-3-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone

A solution of9-aza-1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (64 mg,0.19 mmol), 4-isopropoxy-3-methyl-benzoic acid (45 mg, 0.23 mmol), HATU(89 mg, 0.23 mmol) and iPr₂NEt (169 μL 0.97 mmol) in DMF (0.5 mL) wasstirred at room temperature for 16 hours. Purification by HPLC (10-90%MeOH in Water (HCl modifier)) afforded the HCl salt of the product. Thismaterial was taken up in EtOAc and washed with satuarated aqueous Na₂CO₃(2×), brine, dried over Na₂SO₄ and evaporated to dryness to give9-aza-(4-isopropoxy-3-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(8 mg, 18%) as a white solid. ESI-MS m/z calc. 432.2. found 433.5(M+1)⁺; Retention time: 1.91 minutes (3 min run). NMR (400 MHz, CDCl₃) δ8.19 (dd, J=4.7, 1.3 Hz, 1H), 7.47-7.21 (m, 4H), 7.14 (dd, J=8.2, 4.7Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 4.75-4.48 (m, J=12.0, 5.9 Hz, 1H), 4.36(s, J=7.9 Hz, 3H), 3.44 (s br, 2H), 2.22 (s, J=7.5 Hz, 3H), 2.16 (s br,2H), 1.94 (s br, 2H), 1.70 (s br, 2H), 1.36 (d, J=6.9 Hz, 6H).

The following compounds were prepared using procedures reported above:

Product Name Amine or Amine•HCl Carboxylic Acid (4-(2-methoxyethoxy)-3-spiro[benzo[b]pyrrolo[1,2- 4-(2-methoxyethoxy)-3-methylphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-methylbenzoic acid 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone 2-(2-methoxyethoxy)-5-spiro[benzo[b]pyrrolo[1,2- 3-cyano-4-(2- (spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- methoxyethoxy)benzoic acid d][1,4]oxazine-4,4′-piperidine] piperidine]-1′- ylcarbonyl)benzonitrile (3-chloro-4-(2-spiro[benzo[b]pyrrolo[1,2- 3-chloro-4-(2-methoxyethoxy)phenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-methoxyethoxy)benzoic acid 2- piperidine] d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (4-(isopentyloxy)-3-spiro[benzo[b]pyrrolo[1,2- 4-(isopentyloxy)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-methoxybenzoic acid 2-d][1,4]oxazine- piperidine] 4,4′-piperidine]-1′-yl)methanone (4-(cyclopentyloxy)-3- spiro[benzo[b]pyrrolo[1,2-4-(cyclopentyloxy)-3- methoxyphenyl)(spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- methoxybenzoic acid 2-d][1,4]oxazine- piperidine]4,4′-piperidine]-1′- yl)methanone (4-tert-butyl-3-spiro[benzo[b]pyrrolo[1,2- 4-tert-butyl-3-methoxybenzoicmethoxyphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′- acid2-d][1,4]oxazine- piperidine] 4,4′-piperidine]-1′- yl)methanone2-propoxy-5- spiro[benzo[b]pyrrolo[1,2- 3-cyano-4-propoxybenzoic acid(spiro[benzo[b]pyrrolo[1,2- d][1,4]oxazine-4,4′- d][1,4]oxazine-4,4′-piperidine] piperidine]-1′- ylcarbonyl)benzonitrile (3-methyl-4-spiro[benzo[b]pyrrolo[1,2- 3-methyl-4-propoxybenzoicpropoxyphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′- acid2-d][1,4]oxazine- piperidine] 4,4′-piperidine]-1′- yl)methanone(4-isopropoxy-3- spiro[benzo[b]pyrrolo[1,2- 4-isopropoxy-3-methylbenzoicmethylphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′- acid2-d][1,4]oxazine-4,4′- piperidine] piperidine]-1′-yl)methanone(3-methoxy-4-(2- spiro[benzo[b]pyrrolo[1,2- 3-methoxy-4-(2-methoxyethoxy)phenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-methoxyethoxy)benzoic acid 2- piperidine] d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone 2-isopropoxy-5- spiro[benzo[b]pyrrolo[1,2-3-carbamoyl-4- (spiro[benzo[b]pyrrolo[1,2- d][1,4]oxazine-4,4′-isopropoxybenzoic acid d][1,4]oxazine-4,4′- piperidine] piperidine]-1′-ylcarbonyl)benzamide 2-propoxy-5- spiro[benzo[b]pyrrolo[1,2-3-carbamoyl-4-propoxybenzoic (spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- acid d][1,4]oxazine-4,4′- piperidine]piperidine]-1′- ylcarbonyl)benzamide (4-methoxy-3-spiro[benzo[b]pyrrolo[1,2- 4-methoxy-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-(trifluoromethyl)benzoic acid 2- piperidine] d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (4-isobutoxy-3- spiro[benzo[b]pyrrolo[1,2-4-isobutoxy-3-methoxybenzoic methoxyphenyl)(spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- acid 2-d][1,4]oxazine- piperidine]4,4′-piperidine]-1′- yl)methanone (3-chloro-4-spiro[benzo[b]pyrrolo[1,2- 3-chloro-4-methylbenzoic acidmethylphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine] piperidine]-1′-yl)methanone(4-ethyl-3- spiro[benzo[b]pyrrolo[1,2- 4-ethyl-3-methoxybenzoic acidmethoxyphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-2-d][1,4]oxazine- piperidine] 4,4′-piperidine]-1′- yl)methanone(4-propoxy-3- spiro[benzo[b]pyrrolo[1,2- 4-propoxy-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-(trifluoromethyl)benzoic acid 2- piperidine] d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (4-isopropoxy-3- spiro[benzo[b]pyrrolo[1,2-4-isopropoxy-3- (trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- (trifluoromethyl)benzoic acid 2- piperidine]d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone (4-(2-methoxyethoxy)-3-spiro[benzo[b]pyrrolo[1,2- 4-(2-methoxyethoxy)-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-(trifluoromethyl)benzoic acid 2- piperidine] d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (4-tert-butoxy-3- spiro[benzo[b]pyrrolo[1,2-4-tert-butoxy-3- methoxyphenyl)(spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- methoxybenzoic acid 2-d][1,4]oxazine- piperidine]4,4′-piperidine]-1′- yl)methanone 2-tert-butyl-5-spiro[benzo[b]pyrrolo[1,2- 4-tert-butyl-3-cyanobenzoic(spiro[benzo[b]pyrrolo[1,2- d][1,4]oxazine-4,4′- acidd][1,4]oxazine-4,4′- piperidine] piperidine]-1′- ylcarbonyl)benzonitrile(7- 7- 3-methoxy-4-(2- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, methoxyethoxy)benzoic acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-methoxy- piperidine] 4-(2-methoxyethoxy)phenyl)methanone (7- 7- 4-(2-methoxyethoxy)-3-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,methylbenzoic acid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(2- piperidine] methoxyethoxy)-3-methylphenyl)methanone (7- 7- 4-ethyl-3-methoxybenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-ethyl-3- piperidine] methoxyphenyl)methanone (7- 7-4-isopropoxy-3-methylbenzoic chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(4- piperidine] isopropoxy-3-methylphenyl)methanone (7- 7- 4-isopropoxy-3-methylbenzoicfluorospiro[benzo[b]pyrrolo[1, fluorospiro[benzo[b]pyrrolo[1, acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(4-piperidine] isopropoxy-3- methylphenyl)methanone (7- 7- 3-methoxy-4-(2-fluorospiro[benzo[b]pyrrolo[1, fluorospiro[benzo[b]pyrrolo[1,methoxyethoxy)benzoic acid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-methoxy- piperidine] 4-(2-methoxyethoxy)phenyl)methanone (7- 7- 4-(2-methoxyethoxy)-3-fluorospiro[benzo[b]pyrrolo[1, fluorospiro[benzo[b]pyrrolo[1,methylbenzoic acid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(2- piperidine] methoxyethoxy)-3-methylphenyl)methanone (4-ethyl-3-methoxyphenyl)(7- 7-4-ethyl-3-methoxybenzoic acid fluorospiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone piperidine](4-(2-ethoxyethoxy)-3- spiro[benzo[b]pyrrolo[1,2- 4-(2-ethoxyethoxy)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-methoxybenzoic acid 2-d][1,4]oxazine- piperidine] 4,4′-piperidine]-1′-yl)methanone (R)-(3-methoxy-4- spiro[benzo[b]pyrrolo[1,2-(R)-3-methoxy-4- (tetrahydrofuran-3- d][1,4]oxazine-4,4′-(tetrahydrofuran-3- yloxy)phenyl)(spiro[benzo[b]pyrrolo[1, piperidine]yloxy)benzoic acid 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone(7- 7- 4-propoxy-3- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, (trifluoromethyl)benzoic acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-propoxy-3- piperidine](trifluoromethyl)phenyl)methanone (7- 7- 4-propoxy-3-fluorospiro[benzo[b]pyrrolo[1, fluorospiro[benzo[b]pyrrolo[1,(trifluoromethyl)benzoic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(4-propoxy-3- piperidine](trifluoromethyl)phenyl)methanone (3-methoxy-4-(3-spiro[benzo[b]pyrrolo[1,2- 3-methoxy-4-(3-methoxypropoxy)phenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-methoxypropoxy)benzoic acid 2- piperidine] d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (4-(3-hydroxypropoxy)-3-spiro[benzo[b]pyrrolo[1,2- 4-(3-hydroxypropoxy)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-methoxybenzoic acid 2-d][1,4]oxazine- piperidine] 4,4′-piperidine]-1′-yl)methanone (4-(2-hydroxyethoxy)-3- spiro[benzo[b]pyrrolo[1,2-4-(2-hydroxyethoxy)-3- methoxyphenyl)(spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- methoxybenzoic acid 2-d][1,4]oxazine- piperidine]4,4′-piperidine]-1′- yl)methanone (4-tert-butoxy-3-spiro[benzo[b]pyrrolo[1,2- 4-tert-butoxy-3-methylbenzoicmethylphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′- acid2-d][1,4]oxazine-4,4′- piperidine] piperidine]-1′-yl)methanone (7- 7-4-(3-methoxypropoxy)-3- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, (trifluoromethyl)benzoic acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(4-(3-piperidine] methoxypropoxy)-3- (trifluoromethyl)phenyl)methanone 5-(7-7- 4-methoxy-3-sulfamoylbenzoic chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-ylcarbonyl)-2- piperidine]methoxybenzenesulfonamide (7- 7- 4-(2-isopropoxyethoxy)-3-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,methoxybenzoic acid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(2- piperidine] isopropoxyethoxy)-3-methoxyphenyl)methanone (4-(3-methoxypropoxy)-3-spiro[benzo[b]pyrrolo[1,2- 4-(3-methoxypropoxy)-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-(trifluoromethyl)benzoic acid 2- piperidine] d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone 2-methoxy-5- spiro[benzo[b]pyrrolo[1,2-4-methoxy-3-sulfamoylbenzoic (spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- acid d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-ylcarbonyl)- benzenesulfonamide (R)-(7- 7-(R)-3-methoxy-4- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, (tetrahydrofuran-3-2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- yloxy)benzoic acidpiperidine]-1′-yl)(3-methoxy- piperidine] 4-(tetrahydrofuran-3-yloxy)phenyl)methanone (R)-(7- 7- (R)-3-methoxy-4-(1-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,methoxypropan-2- 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-yloxy)benzoic acid piperidine]-1′-yl)(3-methoxy- piperidine]4-(1-methoxypropan-2- yloxy)phenyl)methanone (7- 7-3-methoxy-4-((tetrahydrofuran- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-yl)methoxy)benzoic acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-methoxy- piperidine] 4-((tetrahydrofuran-2-yl)methoxy)phenyl)methanone (R)-(3-methoxy-4-(1-spiro[benzo[b]pyrrolo[1,2- (R)-3-methoxy-4-(1- methoxypropan-2-d][1,4]oxazine-4,4′- methoxypropan-2-yloxy)phenyl)(spiro[benzo[b]pyrrolo[1, piperidine] yloxy)benzoic acid2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone (3-methoxy-4-spiro[benzo[b]pyrrolo[1,2- 3-methoxy-4-((tetrahydrofuran-((tetrahydrofuran-2- d][1,4]oxazine-4,4′- 2-yl)methoxy)benzoic acidyl)methoxy)phenyl)(spiro[benzo[b]pyrrolo[1, piperidine] 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone (S)-(7- 7-(S)-3-methoxy-4- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, (tetrahydrofuran-3-2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- yloxy)benzoic acidpiperidine]-1′-yl)(3-methoxy- piperidine] 4-(tetrahydrofuran-3-yloxy)phenyl)methanone (S)-(7- 7- (S)-3-methoxy-4-(1-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,methoxypropan-2- 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-yloxy)benzoic acid piperidine]-1′-yl)(3-methoxy- piperidine]4-(1-methoxypropan-2- yloxy)phenyl)methanone (S)-(3-methoxy-4-(1-spiro[benzo[b]pyrrolo[1,2- (S)-3-methoxy-4-(1- methoxypropan-2-d][1,4]oxazine-4,4′- methoxypropan-2-yloxy)phenyl)(spiro[benzo[b]pyrrolo[1, piperidine] yloxy)benzoic acid2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone (S)-(3-methoxy-4-spiro[benzo[b]pyrrolo[1,2- (S)-3-methoxy-4- (tetrahydrofuran-3-d][1,4]oxazine-4,4′- (tetrahydrofuran-3-yloxy)phenyl)(spiro[benzo[b]pyrrolo[1, piperidine] yloxy)benzoic acid2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone (S)-(4-sec-butoxy-3-spiro[benzo[b]pyrrolo[1,2- (S)-4-sec-butoxy-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-methoxybenzoic acid 2-d][1,4]oxazine- piperidine] 4,4′-piperidine]-1′-yl)methanone (S)-(4-sec-butoxy-3- 7- (S)-4-sec-butoxy-3-methoxyphenyl)(7- chlorospiro[benzo[b]pyrrolo[1, methoxybenzoic acidchlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine] piperidine]-1′-yl)methanone (R)-(7-7- (R)-3-methoxy-4-(2- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, methoxypropoxy)benzoic acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-methoxy- piperidine] 4-(2-methoxypropoxy)phenyl)methanone (4-tert-butyl-3- 7-4-tert-butyl-3-methoxybenzoic methoxyphenyl)(7-chlorospiro[benzo[b]pyrrolo[1, acid chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (S)-(3-methoxy-4-(2-spiro[benzo[b]pyrrolo[1,2- (S)-3-methoxy-4-(2-methoxypropoxy)phenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-methoxypropoxy)benzoic acid 2- piperidine] d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (S)-(7- 7- (S)-3-methoxy-4-(2-fluorospiro[benzo[b]pyrrolo[1, fluorospiro[benzo[b]pyrrolo[1,methoxypropoxy)benzoic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3-methoxy- piperidine] 4-(2-methoxypropoxy)phenyl)methanone (S)-(4-sec-butoxy-3- 7-(S)-4-sec-butoxy-3- methoxyphenyl)(7- fluorospiro[benzo[b]pyrrolo[1,methoxybenzoic acid fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (R)-(3-methoxy-4-(2-spiro[benzo[b]pyrrolo[1,2- (R)-3-methoxy-4-(2-methoxypropoxy)phenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-methoxypropoxy)benzoic acid 2- piperidine] d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (R)-(7- 7- (R)-3-methoxy-4-(2-fluorospiro[benzo[b]pyrrolo[1, fluorospiro[benzo[b]pyrrolo[1,methoxypropoxy)benzoic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3-methoxy- piperidine] 4-(2-methoxypropoxy)phenyl)methanone (4-tert-butyl-3- 7-4-tert-butyl-3-methoxybenzoic methoxyphenyl)(7-fluorospiro[benzo[b]pyrrolo[1, acid fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (7- 7- 4-methoxy-3-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,(trifluoromethyl)benzoic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(4-methoxy- piperidine] 3-(trifluoromethyl)phenyl)methanone (7- 7- 4-methoxy-3-fluorospiro[benzo[b]pyrrolo[1, fluorospiro[benzo[b]pyrrolo[1,(trifluoromethyl)benzoic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(4-methoxy- piperidine] 3-(trifluoromethyl)phenyl)methanone (3,4- spiro[benzo[b]pyrrolo[1,2-3,4-dimethylbenzoic acid dimethylphenyl)(spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- 2-d][1,4]oxazine- piperidine] 4,4′-piperidine]-1′-yl)methanone (7- 7- 3,4-dimethylbenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3,4-piperidine] dimethylphenyl)methanone (3,4-dimethylphenyl)(7- 7-3,4-dimethylbenzoic acid fluorospiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone piperidine] (7- 7-4-(2-hydroxypropan-2-yl)-3- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, methoxybenzoic acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(4-(2-piperidine] hydroxypropan-2-yl)-3- methoxyphenyl)methanone (7- 7-4-(2-hydroxypropan-2-yl)-3- fluorospiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, methoxybenzoic acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(4-(2-piperidine] hydroxypropan-2-yl)-3- methoxyphenyl)methanone2-tert-butyl-5-(7- 7- 4-tert-butyl-3-cyanobenzoicchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1, acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-piperidine] ylcarbonyl)benzonitrile 2-tert-butyl-5-(7- 7-4-tert-butyl-3-cyanobenzoic fluorospiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′- piperidine]ylcarbonyl)benzonitrile (7- 7- 4-(2-hydroxypropan-2-yl)-3-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,methylbenzoic acid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(2- piperidine] hydroxypropan-2-yl)-3-methylphenyl)methanone (7- 7- 4-(2-hydroxypropan-2-yl)-3-fluorospiro[benzo[b]pyrrolo[1, fluorospiro[benzo[b]pyrrolo[1,methylbenzoic acid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(2- piperidine] hydroxypropan-2-yl)-3-methylphenyl)methanone (4-(2-hydroxypropan-2-yl)-3-spiro[benzo[b]pyrrolo[1,2- 4-(2-hydroxypropan-2-yl)-3-methylphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-methylbenzoic acid 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone phenyl(spiro[benzo[b]pyrrolo[1,spiro[benzo[b]pyrrolo[1,2- benzoic acid 2-d][1,4]oxazine-4,4′-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone piperidine] (7- 7-benzoic acid fluorospiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′- piperidine] yl)(phenyl)methanone(7- 7- benzoic acid chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′- piperidine] yl)(phenyl)methanonespiro[benzo[b]pyrrolo[1,2- spiro[benzo[b]pyrrolo[1,2-2-(trifluoromethoxy)benzoic d][1,4]oxazine-4,4′- d][1,4]oxazine-4,4′-acid piperidine]-1′-yl(2- piperidine] (trifluoromethoxy)phenyl)methanone(7- 7- 2-(trifluoromethoxy)benzoic fluorospiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2- piperidine](trifluoromethoxy)phenyl)methanone (7- 7- 2-(trifluoromethoxy)benzoicchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1, acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2-piperidine] (trifluoromethoxy)phenyl)methanone(3-methyl-4-((tetrahydrofuran- spiro[benzo[b]pyrrolo[1,2-3-methyl-4-((tetrahydrofuran-2- 2- d][1,4]oxazine-4,4′-yl)methoxy)benzoic acid yl)methoxy)phenyl)(spiro[benzo[b]pyrrolo[1,piperidine] 2- d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone (7- 7-3-methyl-4-((tetrahydrofuran-2- fluorospiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, yl)methoxy)benzoic acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-methyl-4- piperidine] ((tetrahydrofuran-2-yl)methoxy)phenyl)methanone (7- 7- 3-methyl-4-((tetrahydrofuran-2-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,yl)methoxy)benzoic acid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-methyl-4- piperidine] ((tetrahydrofuran-2-yl)methoxy)phenyl)methanone (7- 7- 3-methoxy-4-((tetrahydrofuran-fluorospiro[benzo[b]pyrrolo[1, fluorospiro[benzo[b]pyrrolo[1,2-yl)methoxy)benzoic acid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-methoxy- piperidine] 4-((tetrahydrofuran-2-yl)methoxy)phenyl)methanone (S)-(7- 7- (S)-3-methoxy-4-(1-fluorospiro[benzo[b]pyrrolo[1, fluorospiro[benzo[b]pyrrolo[1,methoxypropan-2- 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-yloxy)benzoic acid piperidine]-1′-yl)(3-methoxy- piperidine]4-(1-methoxypropan-2- yloxy)phenyl)methanone (R)-(7- 7- (R)-3-methoxy-4-fluorospiro[benzo[b]pyrrolo[1, fluorospiro[benzo[b]pyrrolo[1,(tetrahydrofuran-3- 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-yloxy)benzoic acid piperidine]-1′-yl)(3-methoxy- piperidine]4-(tetrahydrofuran-3- yloxy)phenyl)methanone (R)-(7- 7-(R)-3-methoxy-4-(1- fluorospiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, methoxypropan-2- 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- yloxy)benzoic acid piperidine]-1′-yl)(3-methoxy-piperidine] 4-(1-methoxypropan-2- yloxy)phenyl)methanone (S)-(7- 7-(S)-3-methoxy-4- fluorospiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, (tetrahydrofuran-3-2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- yloxy)benzoic acidpiperidine]-1′-yl)(3-methoxy- piperidine] 4-(tetrahydrofuran-3-yloxy)phenyl)methanone (R)-(4-((2,2-dimethyl-1,3-spiro[benzo[b]pyrrolo[1,2- (R)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3- d][1,4]oxazine-4,4′- dioxolan-4-yl)methoxy)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1, piperidine] methoxybenzoic acid2-d][1,4]oxazine- 4,4′-piperidine]-1′- yl)methanone (R)-(7- 7-(R)-4-((2,2-dimethyl-1,3- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, dioxolan-4-yl)methoxy)-3-2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- methoxybenzoic acidpiperidine]-1′-yl)(4-((2,2- piperidine] dimethyl-1,3-dioxolan-4-yl)methoxy)-3- methoxyphenyl)methanone (R)-(4-sec-butoxy-3-spiro[benzo[b]pyrrolo[1,2- (R)-4-sec-butoxy-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-methoxybenzoic acid 2-d][1,4]oxazine- piperidine] 4,4′-piperidine]-1′-yl)methanone (R)-(4-sec-butoxy-3- 7- (R)-4-sec-butoxy-3-methoxyphenyl)(7- chlorospiro[benzo[b]pyrrolo[1, methoxybenzoic acidchlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine] piperidine]-1′-yl)methanone(R)-(4-sec-butoxy-3- 7- (R)-4-sec-butoxy-3- methoxyphenyl)(7-fluorospiro[benzo[b]pyrrolo[1, methoxybenzoic acidfluorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine] piperidine]-1′-yl)methanone2-(2-methoxy-4- spiro[benzo[b]pyrrolo[1,2- 4-(2-cyanopropan-2-yloxy)-3-(spiro[benzo[b]pyrrolo[1,2- d][1,4]oxazine-4,4′- methoxybenzoic acidd][1,4]oxazine-4,4′- piperidine] piperidine]-1′- ylcarbonyl)phenoxy)-2-methylpropanenitrile (4-bromo-3-fluorophenyl)(7- 7-4-bromo-3-fluorobenzoic acid chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone piperidine]4-(7-chloro-1- 7-chloro-1- 1-methyl-2-oxo-1,2-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,(trifluoromethyl)spiro[benzo[b]pyrrolo[1, dihydropyridine-4-carboxylic2-d][1,4]oxazine- 2- acid 4,4′-piperidine]-1′-ylcarbonyl)-d][1,4]oxazine-4,4′- 1-methylpyridin-2(1H)-one piperidine] 5-(7- 7-1-methyl-6-oxo-1,6- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, dihydropyridine-3-carboxylic2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- acidpiperidine]-1′-ylcarbonyl)-1- piperidine] methylpyridin-2(1H)-one (7- 7-3-fluoro-2-hydroxybenzoic acid chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3-fluoro-2- piperidine]hydroxyphenyl)methanone (3-chloro-2-hydroxyphenyl)(7- 7-3-chloro-2-hydroxybenzoic chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone piperidine](4-bromophenyl)(7- 7- 4-bromobenzoic acid chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone piperidine] 3-(7- 7-1-methyl-2-oxo-1,2- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, dihydropyridine-3-carboxylic2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- acidpiperidine]-1′-ylcarbonyl)-1- piperidine] methylpyridin-2(1H)-one 3-(7-7- 1,6-dimethyl-2-oxo-1,2- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, dihydropyridine-3-carboxylic2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- acidpiperidine]-1′-ylcarbonyl)-1,6- piperidine] dimethylpyridin-2(1H)-one3-(7- 7- 6-isopropyl-2-oxo-1,2- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, dihydropyridine-3-carboxylic2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- acidpiperidine]-1′-ylcarbonyl)-6- piperidine] isopropylpyridin-2(1H)-one (7-7- 2-methylbenzo[d]oxazole-7- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, carboxylic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2- piperidine]methylbenzo[d]oxazol-7- yl)methanone 4-(7- 7- 1-isopropyl-2-oxo-1,2-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,dihydropyridine-4-carboxylic 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- acid piperidine]-1′-ylcarbonyl)-1- piperidine]isopropylpyridin-2(1H)-one 3-(7- 7- 4,6-dimethyl-2-oxo-1,2-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,dihydropyridine-3-carboxylic 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- acid piperidine]-1′-ylcarbonyl)-4,6- piperidine]dimethylpyridin-2(1H)-one 3-(7- 7- 1-ethyl-2-oxo-1,2-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,dihydropyridine-3-carboxylic 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- acid piperidine]-1′-ylcarbonyl)-1- piperidine]ethylpyridin-2(1H)-one 1′-(2- spiro[benzo[b]pyrrolo[1,2-2-(difluoromethyl)benzoic acid(difluoromethyl)benzoyl)spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′- 2-piperidine]-1-carbonitrile d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile 1′-(3-fluoro-4- spiro[benzo[b]pyrrolo[1,2-3-fluoro-4-isopropoxybenzoic isopropoxybenzoyl)spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- acid 2- piperidine]-1-carbonitriled][1,4]oxazine-4,4′- piperidine]-1-carbonitrile 1′-(2-fluoro-6-spiro[benzo[b]pyrrolo[1,2- 2-fluoro-6-methoxybenzoicmethoxybenzoyl)spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′- acid2-d][1,4]oxazine- piperidine]-1-carbonitrile4,4′-piperidine]-1-carbonitrile 1′-(2- spiro[benzo[b]pyrrolo[1,2-spiro[benzo[b]pyrrolo[1,2-(difluoromethoxy)benzoyl)spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-d][1,4]oxazine-4,4′-piperidine]- 2- piperidine]-1-carbonitrile1-carbonitrile d][1,4]oxazine-4,4′- piperidine]-1-carbonitrile1′-(2-fluoro-4- spiro[benzo[b]pyrrolo[1,2- 2-fluoro-4-isopropoxybenzoicisopropoxybenzoyl)spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′- acid 2-piperidine]-1-carbonitrile d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile 1′-(3-chloro-4- spiro[benzo[b]pyrrolo[1,2-3-chloro-4-methylbenzoic acid methylbenzoyl)spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- 2-d][1,4]oxazine- piperidine]-1-carbonitrile4,4′-piperidine]-1-carbonitrile 1′-(4-isopropoxy-3-spiro[benzo[b]pyrrolo[1,2- 4-isopropoxy-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-methoxybenzoic acid 2-d][1,4]oxazine- piperidine]-1-carbonitrile4,4′-piperidine]-1-carbonitrile 1′-(4- spiro[benzo[b]pyrrolo[1,2-4-(isopropylsulfonyl)benzoic(isopropylsulfonyl)benzoyl)spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-acid 2- piperidine]-1-carbonitrile d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile 1′-(4-bromo-3- spiro[benzo[b]pyrrolo[1,2-4-bromo-3-methoxybenzoic methoxybenzoyl)spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- acid 2-d][1,4]oxazine- piperidine]-1-carbonitrile4,4′-piperidine]-1-carbonitrile 1′-(3-fluoro-2-spiro[benzo[b]pyrrolo[1,2- 3-fluoro-2-methoxybenzoicmethoxybenzoyl)spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′- acid2-d][1,4]oxazine- piperidine]-1-carbonitrile4,4′-piperidine]-1-carbonitrile 1′-(5-fluoro-2-spiro[benzo[b]pyrrolo[1,2- 5-fluoro-2-methoxybenzoicmethoxybenzoyl)spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′- acid2-d][1,4]oxazine- piperidine]-1-carbonitrile4,4′-piperidine]-1-carbonitrile 1′-(4- spiro[benzo[b]pyrrolo[1,2- 4-(difluoromethylsulfonyl)benzoyl)spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- (difluoromethylsulfonyl)benzoic 2-piperidine]-1-carbonitrile acid d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile 7-chloro-1′-(3-fluoro-2- 7-3-fluoro-2-methoxybenzoic methoxybenzoyl)spiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-2-d][1,4]oxazine-4,4′- 4,4′-piperidine]-1-carbonitrilepiperidine]-1-carbonitrile 7-chloro-1′-(5-fluoro-2- 7-5-fluoro-2-methoxybenzoic methoxybenzoyl)spiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-2,d][1,4]oxazine-4,4′- 4,4′-piperidine]-1-carbonitrilepiperidine]-1-carbonitrile 7-chloro-1′-(4- 7-4-(isopropylsulfonyl)benzoic(isopropylsulfonyl)benzoyl)spiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2- 2-d][1,4]oxazine-4,4′-d][1,4]oxazine-4,4′- piperidine]-1-carbonitrilepiperidine]-1-carbonitrile 1′-(4-tert-butoxy-3-spiro[benzo[b]pyrrolo[1,2- 4-tert-butoxy-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-methoxybenzoic acid 2-d][1,4]oxazine- piperidine]-1-carbonitrile4,4′-piperidine]-1-carbonitrile 1′-(3-ethoxy-2-spiro[benzo[b]pyrrolo[1,2- 3-ethoxy-2-fluorobenzoic acidfluorobenzoyl)spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1-carbonitrilepiperidine]-1-carbonitrile 1′-(4- 3- 4-(isopropylsulfonyl)benzoic(isopropylsulfonyl)benzoyl)-3- methylspiro[benzo[b]pyrrolo[1, acidmethylspiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1-carbonitrilepiperidine]-1-carbonitrile 1′-(4-(tert- spiro[benzo[b]pyrrolo[1,2-4-(tert-butylsulfonyl)benzoicbutylsulfonyl)benzoyl)spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′- acid2- piperidine]-1-carbonitrile d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile 1′-(4-isobutoxy-3- spiro[benzo[b]pyrrolo[1,2-4-isobutoxy-3-methoxybenzoic methoxybenzoyl)spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- acid 2-d][1,4]oxazine- piperidine]-1-carbonitrile4,4′-piperidine]-1-carbonitrile 1′-(4-tert- spiro[benzo[b]pyrrolo[1,2-4-tert-butylbenzoic acid butylbenzoyl)spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1-carbonitrilepiperidine]-1-carbonitrile 1′-(4-methoxy-3- spiro[benzo[b]pyrrolo[1,2-4-methoxy-3- (trifluoromethyl)benzoyl)spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- (trifluoromethyl)benzoic acid 2-piperidine]-1-carbonitrile d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile 1′-(3-(hydroxymethyl)-4-spiro[benzo[b]pyrrolo[1,2- 3-(hydroxymethyl)-4-isopropoxybenzoyl)spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-isopropoxybenzoic acid 2- piperidine]-1-carbonitriled][1,4]oxazine-4,4′- piperidine]-1-carbonitrile 1′-(3-(hydroxymethyl)-4-7- 3-(hydroxymethyl)-4- isopropoxybenzoyl)-7-methylspiro[benzo[b]pyrrolo[1, isopropoxybenzoic acidmethylspiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1-carbonitrilepiperidine]-1-carbonitrile 1′-(3-methyl-4- spiro[benzo[b]pyrrolo[1,2-3-methyl-4- (methylsulfonyl)benzoyl)spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- (methylsulfonyl)benzoic acid 2-piperidine]-1-carbonitrile d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile 1′-(4- spiro[benzo[b]pyrrolo[1,2-4-(isobutylsulfonyl)benzoic(isobutylsulfonyl)benzoyl)spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-acid 2- piperidine]-1-carbonitrile d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile 7-chloro-1′-(4-isopropoxy-3- 7-4-isopropoxy-3-methylbenzoic methylbenzoyl)spiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-2-d][1,4]oxazine-4,4′- 4,4′-piperidine]-1- piperidine]-1-carbaldehydecarbaldehyde 9-fluoro-1′-(4-isopropoxy-3- 9-4-isopropoxy-3-methylbenzoic methylbenzoyl)spiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-2-d][1,4]oxazine-4,4′- 4,4′-piperidine]-1-carbonitrilepiperidine]-1-carbonitrile (4-isopropoxy-3- spiro[benzo[b]pyrrolo[1,2-4-isopropoxy-3- methoxyphenyl)(spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- methoxybenzoic acid 2-d][1,4]oxazine- piperidine]4,4′-piperidine]-1′- yl)methanone 1′-(4- 7- 4-(isopropylsulfonyl)benzoic(isopropylsulfonyl)benzoyl)-7- methylspiro[benzo[b]pyrrolo[1, acidmethylspiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1-carbonitrilepiperidine]-1-carbonitrile 7-methyl-1′-(3-methyl-4- 7- 3-methyl-4-(methylsulfonyl)benzoyl)spiro[benzo[b]pyrrolo[1,methylspiro[benzo[b]pyrrolo[1, (methylsulfonyl)benzoic acid 2-2-d][1,4]oxazine-4,4′- d][1,4]oxazine-4,4′- piperidine]-1-carbonitrilepiperidine]-1-carbonitrile (4- spiro[benzo[b]pyrrolo[1,2-4-(isopropylsulfonyl)benzoic(isopropylsulfonyl)phenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-acid 2- piperidine] d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone(4-(tert- spiro[benzo[b]pyrrolo[1,2- 4-(tert-butylsulfonyl)benzoicbutylsulfonyl)phenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′- acid2- piperidine] d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone(4-bromo-3- 7- 4-bromo-3-methoxybenzoic methoxyphenyl)(7-chlorospiro[benzo[b]pyrrolo[1, acid chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (4- 1- 4- (difluoromethylsulfonyl)phenyl)(1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,(difluoromethylsulfonyl)benzoic(trifluoromethyl)spiro[benzo[b]pyrrolo[1, 2- acid 2-d][1,4]oxazine-d][1,4]oxazine-4,4′- 4,4′-piperidine]-1′- piperidine] yl)methanone(4-(isobutylsulfonyl)phenyl)(1- 1- 4-(isobutylsulfonyl)benzoic(trifluoromethyl)spiro[benzo[b]pyrrolo[1,(trifluoromethyl)spiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine- 2-4,4′-piperidine]-1′- d][1,4]oxazine-4,4′- yl)methanone piperidine]N-methyl-4-(1- 1- 4-(N-methylsulfamoyl)benzoic(trifluoromethyl)spiro[benzo[b]pyrrolo[1,(trifluoromethyl)spiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine- 2-4,4′-piperidine]-1′- d][1,4]oxazine-4,4′- ylcarbonyl)benzenesulfonamidepiperidine] N-ethyl-4-(1- 1- 4-(N-ethylsulfamoyl)benzoic(trifluoromethyl)spiro[benzo[b]pyrrolo[1,(trifluoromethyl)spiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine- 2-4,4′-piperidine]-1′- d][1,4]oxazine-4,4′- ylcarbonyl)benzenesulfonamidepiperidine] (4- 1- 4-(isopropylsulfonyl)benzoic(isopropylsulfonyl)phenyl)(1- (trifluoromethyl)spiro[benzo[b]pyrrolo[1,acid (trifluoromethyl)spiro[benzo[b]pyrrolo[1, 2- 2-d][1,4]oxazine-d][1,4]oxazine-4,4′- 4,4′-piperidine]-1′- piperidine] yl)methanone (1-1- 4-(isopropylsulfonyl)benzoic (difluoromethyl)spiro[benzo[b]pyrrolo[1,(difluoromethyl)spiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine- 2-4,4′-piperidine]-1′-yl)(4- d][1,4]oxazine-4,4′-(isopropylsulfonyl)phenyl)methanone piperidine](3-ethoxy-2-fluorophenyl)(1- 1- 3-ethoxy-2-fluorobenzoic acid(methylsulfonyl)spiro[benzo[b]pyrrolo[1,(methylsulfonyl)spiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine- 2-4,4′-piperidine]-1′- d][1,4]oxazine-4,4′- yl)methanone piperidine](4-tert-butylphenyl)(1- 1- 4-tert-butylbenzoic acid(methylsulfonyl)spiro[benzo[b]pyrrolo[1,(methylsulfonyl)spiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine- 2-4,4′-piperidine]-1′- d][1,4]oxazine-4,4′- yl)methanone piperidine](3-chloro-4-methylphenyl)(1- 1- 3-chloro-4-methylbenzoic acid(methylsulfonyl)spiro[benzo[b]pyrrolo[1,(methylsulfonyl)spiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine- 2-4,4′-piperidine]-1′- d][1,4]oxazine-4,4′- yl)methanone piperidine] (2-1- 2-(difluoromethoxy)benzoic (difluoromethoxy)phenyl)(1-(methylsulfonyl)spiro[benzo[b]pyrrolo[1, acid(methylsulfonyl)spiro[benzo[b]pyrrolo[1, 2- 2-d][1,4]oxazine-d][1,4]oxazine-4,4′- 4,4′-piperidine]-1′- piperidine] yl)methanone(2-fluoro-4- 1- 2-fluoro-4-isopropoxybenzoic isopropoxyphenyl)(1-(methylsulfonyl)spiro[benzo[b]pyrrolo[1, acid(methylsulfonyl)spiro[benzo[b]pyrrolo[1, 2- 2-d][1,4]oxazine-d][1,4]oxazine-4,4′- 4,4′-piperidine]-1′- piperidine] yl)methanone(3-fluoro-4- 1- 3-fluoro-4-isopropoxybenzoic isopropoxyphenyl)(1-(methylsulfonyl)spiro[benzo[b]pyrrolo[1, acid(methylsulfonyl)spiro[benzo[b]pyrrolo[1, 2- 2-d][1,4]oxazine-d][1,4]oxazine-4,4′- 4,4′-piperidine]-1′- piperidine] yl)methanone(4-isopropoxy-3- 1- 4-isopropoxy-3- methoxyphenyl)(1-(methylsulfonyl)spiro[benzo[b]pyrrolo[1, methoxybenzoic acid(methylsulfonyl)spiro[benzo[b]pyrrolo[1, 2- 2-d][1,4]oxazine-d][1,4]oxazine-4,4′- 4,4′-piperidine]-1′- piperidine] yl)methanone (1-1- 4-(isopropylsulfonyl)benzoic fluorospiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(4- piperidine](isopropylsulfonyl)phenyl)methanone (4-isopropoxy-3- 9- 4-isopropoxy-3-methylphenyl)(9- methylspiro[benzo[b]pyrrolo[1, methoxybenzoic acidmethylspiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine] piperidine]-1′-yl)methanone (4-spiro[benzo[b]imidazo[1,2- 4-(isopropylsulfonyl)benzoic(isopropylsulfonyl)phenyl)(spiro[benzo[b]imidazo[1, d][1,4]oxazine-4,4′-acid 2- piperidine] d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone(4-tert-butoxy-3- spiro[benzo[b]imidazo[1,2- 4-tert-butoxy-3-methoxyphenyl)(spiro[benzo[b]imidazo[1, d][1,4]oxazine-4,4′-methoxybenzoic acid 2-d][1,4]oxazine- piperidine] 4,4′-piperidine]-1′-yl)methanone (4-isopropoxy-3- spiro[benzo[b]imidazo[1,2-4-isopropoxy-3-methylbenzoic methylphenyl)(spiro[benzo[b]imidazo[1,d][1,4]oxazine-4,4′- acid 2-d][1,4]oxazine- piperidine]4,4′-piperidine]-1′- yl)methanone 1-methyl-4- spiro[benzo[b]pyrrolo[1,2-1-methyl-2-oxo-pyridine-4- (spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- carboxylic acid d][1,4]oxazine-4,4′- piperidine]piperidine]-1′- ylcarbonyl)pyridin-2(1H)-one 2,4-dimethoxy-5-spiro[benzo[b]pyrrolo[1,2- 5-formyl-2,4-dimethoxybenzoic(spiro[benzo[b]pyrrolo[1,2- d][1,4]oxazine-4,4′- acidd][1,4]oxazine-4,4′- piperidine] piperidine]-1′- ylcarbonyl)benzaldehyde(4-((1R,2R)-2- spiro[benzo[b]pyrrolo[1,2- 4-((1R,2R)-2-hydroxycyclopentyloxy)-3- d][1,4]oxazine-4,4′- hydroxycyclopentyloxy)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1, piperidine] methoxybenzoic acid2-d][1,4]oxazine- 4,4′-piperidine]-1′- yl)methanone(4-(3-hydroxycyclopentyloxy)- spiro[benzo[b]pyrrolo[1,2-4-(3-hydroxycyclopentoxy)-3- 3- d][1,4]oxazine-4,4′- methoxy-benzoicacid methoxyphenyl)(spiro[benzo[b]pyrrolo[1, piperidine]2-d][1,4]oxazine- 4,4′-piperidine]-1′- yl)methanone 2-methyl-4-spiro[benzo[b]pyrrolo[1,2- 4-cyano-3-methyl-benzoic acid(spiro[benzo[b]pyrrolo[1,2- d][1,4]oxazine-4,4′- d][1,4]oxazine-4,4′-piperidine] piperidine]-1′- ylcarbonyl)benzonitrile(2-fluoro-5-methoxy-4-(2- spiro[benzo[b]pyrrolo[1,2-2-fluoro-5-methoxy-4-(2- methoxyethoxy)phenyl)(spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- methoxyethoxy)benzoic acid 2- piperidine]d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone 2-(2-methoxy-4-spiro[benzo[b]pyrrolo[1,2- 4-(carbamoylmethoxy)-3-(spiro[benzo[b]pyrrolo[1,2- d][1,4]oxazine-4,4′- methoxy-benzoic acidd][1,4]oxazine-4,4′- piperidine] piperidine]-1′-ylcarbonyl)phenoxy)acetamide (2-(piperidin-1-yl)pyridin-4-spiro[benzo[b]pyrrolo[1,2- 2-(1-piperidyl)pyridine-4-yl)(spiro[benzo[b]pyrrolo[1,2- d][1,4]oxazine-4,4′- carboxylic acidd][1,4]oxazine-4,4′- piperidine] piperidine]-1′-yl)methanone(3-methoxy-4-(2-methoxy-2- spiro[benzo[b]pyrrolo[1,2-3-methoxy-4-(2-methoxy-2- methylpropoxy)phenyl)(spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- methyl-propoxy)-benzoic acid 2- piperidine]d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone (3-methoxy-4-(2-spiro[benzo[b]pyrrolo[1,2- 3-methoxy-4-[2-(trifluoromethoxy)ethoxy)phenyl)(spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- (trifluoromethoxy)ethoxy]benzoic 2- piperidine]acid d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone (3-methoxy-4-spiro[benzo[b]pyrrolo[1,2- 3-methoxy-4-propoxy-benzoicpropoxyphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′- acid2-d][1,4]oxazine- piperidine] 4,4′-piperidine]-1′- yl)methanone(4-ethyl-3- spiro[benzo[b]pyrrolo[1,2- 4-ethyl-3-hydroxy-benzoic acidhydroxyphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-2-d][1,4]oxazine- piperidine] 4,4′-piperidine]-1′- yl)methanone(4-tert-butyl-3- spiro[benzo[b]pyrrolo[1,2-3-hydroxy-4-tert-butyl-benzoic hydroxyphenyl)(spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- acid 2-d][1,4]oxazine- piperidine]4,4′-piperidine]-1′- yl)methanone (2-fluoro-4,5-spiro[benzo[b]pyrrolo[1,2- 2-fluoro-4,5-dimethoxy-dimethoxyphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′- benzoicacid 2-d][1,4]oxazine- piperidine] 4,4′-piperidine]-1′- yl)methanone(S)-(4-((2,2-dimethyl-1,3- spiro[benzo[b]pyrrolo[1,2-(S)-4-((2,2-dimethyl-1,3- dioxolan-4-yl)methoxy)-3- d][1,4]oxazine-4,4′-dioxolan-4-yl)methoxy)-3- methoxyphenyl)(spiro[benzo[b]pyrrolo[1,piperidine] methoxybenzoic acid 2-d][1,4]oxazine- 4,4′-piperidine]-1′-yl)methanone (6-(piperidin-1-yl)pyridin-3- spiro[benzo[b]pyrrolo[1,2-6-(1-piperidyl)pyridine-3- yl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- carboxylic acid d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (2-methoxy-3- spiro[benzo[b]pyrrolo[1,2-2-methoxy-3-methyl-benzoic methylphenyl)(spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- acid 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (4-(3-hydroxyoxetan-3-yl)-3-spiro[benzo[b]pyrrolo[1,2- 4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1, d][1,4]oxazine-4,4′-methoxy-benzoic acid 2-d][1,4]oxazine- piperidine] 4,4′-piperidine]-1′-yl)methanone (S)-(4-((2,2-dimethyl-1,3- spiro[benzo[b]pyrrolo[1,2-(S)-4-((2,2-dimethyl-1,3- dioxolan-4-yl)methoxy)-3- d][1,4]oxazine-4,4′-dioxolan-4-yl)methoxy)-3- methoxyphenyl)(spiro[benzo[b]pyrrolo[1,piperidine] methoxybenzoic acid 2-d][1,4]oxazine- 4,4′-piperidine]-1′-yl)methanone (4-ethyl-3- spiro[benzo[b]pyrrolo[1,2-4-ethyl-3-methyl-benzoic acid methylphenyl)(spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (2-(2-methoxyethoxy)pyridin-spiro[benzo[b]pyrrolo[1,2- 2-(2-methoxyethoxy)pyridine- 4-d][1,4]oxazine-4,4′- 4-carboxylic acid yl)(spiro[benzo[b]pyrrolo[1,2-piperidine] d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone(2-fluoro-5-methoxy-4-(2- 7- 2-fluoro-5-methoxy-4-(2-methoxyethoxy)phenyl)(7- fluorospiro[benzo[b]pyrrolo[1,methoxyethoxy)benzoic acid fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone 2-(4-(7- 7- 4-(carbamoylmethoxy)-3-fluorospiro[benzo[b]pyrrolo[1, fluorospiro[benzo[b]pyrrolo[1,methoxy-benzoic acid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)-2- piperidine] methoxyphenoxy)acetamide 4-(7-7- 4-cyano-3-methyl-benzoic acid fluorospiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-ylcarbonyl)-2- piperidine]methylbenzonitrile 5-(7- 7- 5-formyl-2,4-dimethoxybenzoicfluorospiro[benzo[b]pyrrolo[1, fluorospiro[benzo[b]pyrrolo[1, acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)-2,4- piperidine] dimethoxybenzaldehyde(4-ethyl-3-methylphenyl)(7- 7- 4-ethyl-3-methyl-benzoic acidfluorospiro[benzo[b]pyrrolo[1, fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone piperidine] (7- 7-4-(3-hydroxycyclopentoxy)-3- fluorospiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, methoxy-benzoic acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(4-(3-piperidine] hydroxycyclopentyloxy)-3- methoxyphenyl)methanone (7- 7-4-((1R,2R)-2- fluorospiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, hydroxycyclopentyloxy)-3-2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- methoxybenzoic acidpiperidine]-1′-yl)(4-((1R,2R)- piperidine] 2-hydroxycyclopentyloxy)-3-methoxyphenyl)methanone (7- 7- 4-(3-hydroxyoxetan-3-yl)-3-fluorospiro[benzo[b]pyrrolo[1, fluorospiro[benzo[b]pyrrolo[1,methoxy-benzoic acid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(3- piperidine] hydroxyoxetan-3-yl)-3-methoxyphenyl)methanone (S)-(4-((2,2-dimethyl-1,3- 7-(S)-4-((2,2-dimethyl-1,3- dioxolan-4-yl)methoxy)-3-fluorospiro[benzo[b]pyrrolo[1, dioxolan-4-yl)methoxy)-3-methoxyphenyl)(7- 2-d][1,4]oxazine-4,4′- methoxybenzoic acidfluorospiro[benzo[b]pyrrolo[1, piperidine] 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (7- 7- 3-methoxy-4-(2-methoxy-2-fluorospiro[benzo[b]pyrrolo[1, fluorospiro[benzo[b]pyrrolo[1,methyl-propoxy)-benzoic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3-methoxy- piperidine]4-(2-methoxy-2- methylpropoxy)phenyl)methanone (7- 7-3-methoxy-4-propoxy-benzoic fluorospiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3-methoxy- piperidine]4-propoxyphenyl)methanone (4-ethyl-3-hydroxyphenyl)(7- 7-4-ethyl-3-hydroxy-benzoic acid fluorospiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone piperidine](R)-(4-((2,2-dimethyl-1,3- 7- (R)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3- fluorospiro[benzo[b]pyrrolo[1,dioxolan-4-yl)methoxy)-3- methoxyphenyl)(7- 2-d][1,4]oxazine-4,4′-methoxybenzoic acid fluorospiro[benzo[b]pyrrolo[1, piperidine]2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone(S)-(4-((2,2-dimethyl-1,3- 7- (S)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3- fluorospiro[benzo[b]pyrrolo[1,dioxolan-4-yl)methoxy)-3- methoxyphenyl)(7- 2-d][1,4]oxazine-4,4′-methoxybenzoic acid fluorospiro[benzo[b]pyrrolo[1, piperidine]2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone (4-tert-butyl-3- 7-3-hydroxy-4-tert-butyl-benzoic hydroxyphenyl)(7-fluorospiro[benzo[b]pyrrolo[1, acid fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (2-fluoro-4,5- 7- 2-fluoro-4,5-dimethoxy-dimethoxyphenyl)(7- fluorospiro[benzo[b]pyrrolo[1, benzoic acidfluorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine] piperidine]-1′-yl)methanone (7- 7-2-methoxy-3-methyl-benzoic fluorospiro[benzo[b]pyrrolo[1,fluorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2-methoxy- piperidine]3-methylphenyl)methanone 2-(7- 7- 2-cyanobenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-piperidine] ylcarbonyl)benzonitrile 3-(7- 7- 3-cyanobenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-piperidine] ylcarbonyl)benzonitrile (7- 7- 4-ethyl-3-hydroxy-benzoicacid chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-ethyl-3- piperidine] hydroxyphenyl)methanone(2-chloro-4- 7- 2-chloro-4-methylsulfonyl- (methylsulfonyl)phenyl)(7-chlorospiro[benzo[b]pyrrolo[1, benzoic acidchlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine] piperidine]-1′-yl)methanone 4-(7- 7-1-methyl-2-oxo-pyridine-4- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, carboxylic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-ylcarbonyl)-1- piperidine]methylpyridin-2(1H)-one (7- 7- 4-methoxy-2-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,(trifluoromethyl)benzoic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(4-methoxy- piperidine] 2-(trifluoromethyl)phenyl)methanone (7- 7- 4-(2-hydroxycyclopentoxy)-3-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,methoxy-benzoic acid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-((1R,2R)- piperidine] 2-hydroxycyclopentyloxy)-3-methoxyphenyl)methanone (7- 7- 2-hydroxybenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2-piperidine] hydroxyphenyl)methanone (7- 7- 2-fluoro-4,5-dimethoxy-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1, benzoicacid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(2-fluoro-4,5- piperidine] dimethoxyphenyl)methanone(7- 7- 2,4-dimethoxybenzoic acid chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2,4- piperidine]dimethoxyphenyl)methanone (7- 7- 2,6-dimethoxybenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2,6-piperidine] dimethoxyphenyl)methanone (7- 7- 4-(3-hydroxyoxetan-3-yl)-3-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,methoxy-benzoic acid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(3- piperidine] hydroxyoxetan-3-yl)-3-methoxyphenyl)methanone 3-(7- 7- 3-cyano-5-fluoro-benzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)-5- piperidine] fluorobenzonitrile 2-(4-(7- 7-4-(carbamoylmethoxy)-3- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, methoxy-benzoic acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)-2- piperidine] methoxyphenoxy)acetamide (7-7- 4-ethyl-3-methyl-benzoic acid chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(4-ethyl-3- piperidine]methylphenyl)methanone (7- 7- 3-methoxy-4-(2-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,methylsulfonylethoxy)benzoic 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- acid piperidine]-1′-yl)(3-methoxy- piperidine]4-(2- (methylsulfonyl)ethoxy)phenyl)methanone 4-(7- 7-1-(2-methoxyethyl)-2-oxo- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, pyridine-4-carboxylic acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)-1- piperidine] (2-methoxyethyl)pyridin-2(1H)-one (7- 7- 4-fluoro-3-methoxy-benzoicchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1, acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-fluoro-3- piperidine] methoxyphenyl)methanone(5-chloro-2-methoxyphenyl)(7- 7- 5-chloro-2-methoxy-benzoicchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1, acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone piperidine] (7- 7-2-fluoro-6-methoxy-benzoic chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2-fluoro-6- piperidine]methoxyphenyl)methanone (7- 7- 4-methoxy-2-methyl-benzoicchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1, acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-methoxy- piperidine] 2-methylphenyl)methanone (7-7- 2-methoxy-3-methyl-benzoic chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2-methoxy- piperidine]3-methylphenyl)methanone (7- 7- 4-methoxy-2-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,(trifluoromethoxy)benzoic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(4-methoxy- piperidine] 2-(trifluoromethoxy)phenyl)methanone (4-bromo-3- 7-4-bromo-3-methoxybenzoic methoxyphenyl)(7-chlorospiro[benzo[b]pyrrolo[1, acid chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone methyl 2-(4-(7- 7- 3-methoxy-4-(1-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,methoxycarbonyl-1-methyl- 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-ethyl)-benzoic acid piperidine]-1′-ylcarbonyl)-2- piperidine]methoxyphenyl)-2- methylpropanoate 5-(7- 7-5-formyl-2,4-dimethoxybenzoic chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-ylcarbonyl)-2,4- piperidine]dimethoxybenzaldehyde (7- 7- 4-(3-hydroxycyclopentoxy)-3-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,methoxy-benzoic acid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(3- piperidine] hydroxycyclopentyloxy)-3-methoxyphenyl)methanone (7- 7- 3-methoxy-4-(2-methoxy-2-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,methyl-propoxy)-benzoic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3-methoxy- piperidine]4-(2-methoxy-2- methylpropoxy)phenyl)methanone (7- 7-3-fluoro-5-methoxy-benzoic chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3-fluoro-5- piperidine]methoxyphenyl)methanone (7- 7- 2-ethylbenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2-piperidine] ethylphenyl)methanone (3-chloro-5-methoxyphenyl)(7- 7-3-chloro-5-methoxy-benzoic chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone piperidine] (S)-(7-7- (S)-4-((2,2-dimethyl-1,3- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, dioxolan-4-yl)methoxy)-3-2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- methoxybenzoic acidpiperidine]-1′-yl)(4-((2,2- piperidine] dimethyl-1,3-dioxolan-4-yl)methoxy)-3- methoxyphenyl)methanone (7- 7- 3-fluoro-4-oxetan-3-yloxy-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1, benzoicacid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-fluoro-4- piperidine] (oxetan-3-yloxy)phenyl)methanone (7- 7- 3-methoxy-4-[2-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,(trifluoromethoxy)ethoxy]benzoic 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- acid piperidine]-1′-yl)(3-methoxy- piperidine]4-(2- (trifluoromethoxy)ethoxy)phenyl)methanone (7- 7-4-(3-hydroxyoxetan-3-yl)-3- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, methoxybenzoic acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(4-(3-piperidine] hydroxyoxetan-3-yl)-3- methoxyphenyl)methanone (S)-(7- 7-3-methoxy-4-(2- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, methoxypropoxy)benzoic acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-methoxy- piperidine] 4-(2-methoxypropoxy)phenyl)methanone (7- 7- 2-(difluoromethoxy)benzoicchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1, acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2-piperidine] (difluoromethoxy)phenyl)methanone (7- 7-3-methylsulfonylbenzoic acid chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3- piperidine](methylsulfonyl)phenyl)methanone (7- 7- 2,5-dimethoxybenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2,5-piperidine] dimethoxyphenyl)methanone (3-chlorophenyl)(7- 7-3-chlorobenzoic acid chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone piperidine] (7- 7-3,5-dichlorobenzoic acid chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3,5- piperidine]dichlorophenyl)methanone (7- 7- 3-methoxybenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3-piperidine] methoxyphenyl)methanone (7- 7- 2-fluoro-5-methoxy-4-(2-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,methoxyethoxy)benzoic acid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(2-fluoro-5- piperidine] methoxy-4-(2-methoxyethoxy)phenyl)methanone (7- 7- 2-methoxybenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2-piperidine] methoxyphenyl)methanone (7- 7- 3,5-dimethoxybenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3,5-piperidine] dimethoxyphenyl)methanone (7- 7- 2-methoxy-4-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,(trifluoromethyl)benzoic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2-methoxy- piperidine] 4-(trifluoromethyl)phenyl)methanone (7- 7- 3,5-dimethylbenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3,5-piperidine] dimethylphenyl)methanone (7- 7- 3-(trifluoromethyl)benzoicacid chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3-piperidine] (trifluoromethyl)phenyl)methanone 4-(7- 7-4-cyano-3-methyl-benzoic acid chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-ylcarbonyl)-2- piperidine]methylbenzonitrile (7- 7- 2-methoxy-4-methyl-benzoicchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1, acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(2-methoxy- piperidine] 4-methylphenyl)methanone (7-7- 2-(2-methoxyethoxy)pyridine- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 4-carboxylic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2-(2- piperidine]methoxyethoxy)pyridin-4- yl)methanone (7- 7- 3-ethoxybenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3-piperidine] ethoxyphenyl)methanone (4-chloro-2-(2-(thiophen-2- 7-4-chloro-2-[2-(2- yl)ethyl)phenyl)(7- chlorospiro[benzo[b]pyrrolo[1,thienyl)ethyl]benzoic acid chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (2,4- 7- 2,4-bis(trifluoromethyl)benzoicbis(trifluoromethyl)phenyl)(7- chlorospiro[benzo[b]pyrrolo[1, acidchlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine] piperidine]-1′-yl)methanone(4-chloro-2-methylphenyl)(7- 7- 4-chloro-2-methyl-benzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone piperidine] (4-chloro-2-(2,5-dimethyl-1H- 7-4-chloro-2-(2,5-dimethylpyrrol- pyrrol-1-yl)phenyl)(7-chlorospiro[benzo[b]pyrrolo[1, 1-yl)-benzoic acidchlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine] piperidine]-1′-yl)methanone (3,5- 7-3,5-bis(trifluoromethyl)benzoic bis(trifluoromethyl)phenyl)(7-chlorospiro[benzo[b]pyrrolo[1, acid chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (7- 7- 3,5-di-tert-butylbenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3,5-di-tert- piperidine] butylphenyl)methanone(4-chloro-2- 7- 4-chloro-2-methylsulfonyl- (methylsulfonyl)phenyl)(7-chlorospiro[benzo[b]pyrrolo[1, benzoic acidchlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine] piperidine]-1′-yl)methanone(3-chloro-5-fluorophenyl)(7- 7- 3-chloro-5-fluoro-benzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone piperidine] tert-butyl 5-chloro-2-(7- 7-4-chloro-2-(tert- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, butoxycarbonylamino)-benzoic2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- acid piperidine]-1′-piperidine] ylcarbonyl)phenylcarbamate (2-chloro-4-fluorophenyl)(7- 7-2-chloro-4-fluoro-benzoic acid chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone piperidine] methyl3-(7- 7- 3-methoxycarbonyl-5-(methyl- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, methylsulfonyl-amino)-benzoic2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- acidpiperidine]-1′-ylcarbonyl)-5- piperidine] (N-methylmethylsulfonamido)benzoate (4-chloro-2-fluorophenyl)(7- 7-4-chloro-2-fluoro-benzoic acid chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone piperidine] N-(4-(7-7- 4-acetamido-2-methyl-benzoic chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-ylcarbonyl)-3- piperidine]methylphenyl)acetamide (7- 7- 3-fluorobenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3-piperidine] fluorophenyl)methanone 4-(7- 7- 4-cyano-2-fluoro-benzoicacid chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)-3- piperidine] fluorobenzonitrile (7- 7-3,5-diethoxybenzoic acid chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3,5- piperidine]diethoxyphenyl)methanone (7- 7- 2-fluoro-4-methoxy-benzoicchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1, acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(2-fluoro-4- piperidine] methoxyphenyl)methanone(S)-(7- 7- (S)-4-((2,2-dimethyl-1,3- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, dioxolan-4-yl)methoxy)-3-2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- methoxybenzoic acidpiperidine]-1′-yl)(4-((2,2- piperidine] dimethyl-1,3-dioxolan-4-yl)methoxy)-3- methoxyphenyl)methanone (4-tert-butyl-3- 7-3-hydroxy-4-tert-butyl-benzoic hydroxyphenyl)(7-chlorospiro[benzo[b]pyrrolo[1, acid chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (7- 7- 3-fluoro-5-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,(trifluoromethyl)benzoic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3-fluoro-5- piperidine](trifluoromethyl)phenyl)methanone (7- 7- 3,5-diethylbenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3,5-piperidine] diethylphenyl)methanone (7- 7- 3,5-difluorobenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3,5-piperidine] difluorophenyl)methanone (7- 7- 2-fluoro-4-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,(trifluoromethyl)benzoic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2-fluoro-4- piperidine](trifluoromethyl)phenyl)methanone (7- 7- 4-fluoro-2-methyl-benzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-fluoro-2- piperidine] methylphenyl)methanone (7- 7-2-methyl-4- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, (trifluoromethoxy)benzoic acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(2-methyl-4- piperidine](trifluoromethoxy)phenyl)methanone (7- 7- 2-fluoro-4-methyl-benzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(2-fluoro-4- piperidine] methylphenyl)methanone (7- 7-2,4-dichlorobenzoic acid chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2,4- piperidine]dichlorophenyl)methanone (2-chloro-4-(4H-1,2,4-triazol- 7-2-chloro-4-(1,2,4-triazol-4- 4-yl)phenyl)(7-chlorospiro[benzo[b]pyrrolo[1, yl)benzoic acidchlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine] piperidine]-1′-yl)methanone (7- 7-4-methyl-2- chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, (trifluoromethyl)benzoic acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-methyl-2- piperidine](trifluoromethyl)phenyl)methanone (7- 7- 4-fluoro-2-methoxy-benzoicchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1, acid2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-fluoro-2- piperidine] methoxyphenyl)methanone(2-(2-chloro-1,1,2- 7- 2-(2-chloro-1,1,2-trifluoro- trifluoroethoxy)-4-chlorospiro[benzo[b]pyrrolo[1, ethoxy)-4-methoxy-benzoicmethoxyphenyl)(7- 2-d][1,4]oxazine-4,4′- acidchlorospiro[benzo[b]pyrrolo[1, piperidine] 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (7- 7- 2-methoxy-4-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,(trifluoromethoxy)benzoic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2-methoxy- piperidine] 4-(trifluoromethoxy)phenyl)methanone (7- 7- 3-fluoro-5-methyl-benzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-fluoro-5- piperidine] methylphenyl)methanone (7- 7-2,4-dimethylbenzoic acid chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2,4- piperidine]dimethylphenyl)methanone (4-chloro-2-methoxyphenyl)(7- 7-4-chloro-2-methoxy-benzoic chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone piperidine] (7- 7-3-(trifluoromethoxy)benzoic chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3- piperidine](trifluoromethoxy)phenyl)methanone (2-chloro-4-methylphenyl)(7- 7-2-chloro-4-methyl-benzoic acid chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone piperidine](4-(benzyloxy)-2- 7- 4-benzyloxy-2-chloro-benzoic chlorophenyl)(7-chlorospiro[benzo[b]pyrrolo[1, acid chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone methyl 3-(7- 7- 3-methoxycarbonyl-5-methyl-chlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1, benzoicacid 2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)-5- piperidine] methylbenzoate (7- 7-3-methoxy-4-propoxy-benzoic chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(3-methoxy- piperidine]4-propoxyphenyl)methanone (7- 7- 2,4-difluorobenzoic acidchlorospiro[benzo[b]pyrrolo[1, chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(2,4-piperidine] difluorophenyl)methanone (3-chloro-5- 7- 3-chloro-5-(trifluoromethyl)phenyl)(7- chlorospiro[benzo[b]pyrrolo[1,(trifluoromethyl)benzoic acid chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (1-methyl-1H- 1- 3-methylbenzoic acidspiro[chromeno[4,3- methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)(m-tolyl)methanone(1-methyl-1H- 1- 3-(trifluoromethoxy)benzoic spiro[chromeno[4,3-methylspiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)[3-(trifluoromethoxy)phenyl]- methanone (2-hydroxy-3-methyl-phenyl)- 1-2-hydroxy-3-methyl-benzoic (1-methyl-1H- methylspiro[chromeno[4,3- acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-quinoline-4-carboxylic acid spiro[chromeno[4,3-methylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)(4-quinolyl)methanone(3,4-dimethylphenyl)-(1- 1- 3,4-dimethylbenzoic acid methyl-1H-methylspiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(3-chloro-4-methoxy-phenyl)- 1- 3-chloro-4-methoxy-benzoic (1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-4-propoxybenzoic acid spiro[chromeno[4,3- methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)(4-propoxyphenyl)-methanone (R)-(3-methoxy-4- 1- (R)-3-methoxy-4- (tetrahydrofuran-3-methylspiro[chromeno[4,3- (tetrahydrofuran-3- yloxy)phenyl)(1-methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride yloxy)benzoic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′- yl)methanone[4-(2-methoxyethoxy)-3- 1- 4-(2-methoxyethoxy)-3-methyl-methyl-phenyl]-(1-methyl-1H- methylspiro[chromeno[4,3- benzoic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-ethyl-3-methoxy-phenyl)-1- 4-ethyl-3-methoxy-benzoic acid (1-methyl-1H-methylspiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-isopropoxyphenyl)-(1- 1-4-isopropoxybenzoic acid methyl-1H- methylspiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-4-propoxy-3- spiro[chromeno[4,3- methylspiro[chromeno[4,3-(trifluoromethyl)benzoic acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)[4-propoxy-3-(trifluoromethyl)phenyl]- methanone (3,4-dimethoxyphenyl)-(1- 1-3,4-dimethoxybenzoic acid methyl-1H- methylspiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (S)-(3-methoxy-4-(2- 1-(S)-3-methoxy-4-(2- methoxypropoxy)phenyl)(1- methylspiro[chromeno[4,3-methoxypropoxy)benzoic acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone [3-methoxy-4-(2- 1-3-methoxy-4-(2- methoxyethoxy)phenyl]-(1- methylspiro[chromeno[4,3-methoxyethoxy)benzoic acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-cyclopentoxyphenyl)-(1-1- 4-cyclopentoxybenzoic acid methyl-1H- methylspiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (R)-(3-methoxy-4-(2- 1-(R)-3-methoxy-4-(2- methoxypropoxy)phenyl)(1- methylspiro[chromeno[4,3-methoxypropoxy)benzoic acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-ethoxy-3-methoxy-phenyl)- 1- 4-ethoxy-3-methoxy-benzoic (1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-methoxy-3-methyl-phenyl)- 1- 4-methoxy-3-methyl-benzoic (1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone[4-(1-hydroxy-1-methyl-ethyl)- 1- 4-(1-hydroxy-1-methyl-ethyl)-3-methyl-phenyl]-(1-methyl- methylspiro[chromeno[4,3- 3-methyl-benzoicacid 1H-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone[4-(1-hydroxy-1-methyl-ethyl)- 1- 4-(1-hydroxy-1-methyl-ethyl)-3-methoxy-phenyl]-(1-methyl- methylspiro[chromeno[4,3- 3-methoxy-benzoicacid 1H-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-2-(trifluoromethoxy)benzoic spiro[chromeno[4,3-methylspiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)[2-(trifluoromethoxy)phenyl]- methanone (3-methyl-4-propoxy-phenyl)- 1-3-methyl-4-propoxy-benzoic (1-methyl-1H- methylspiro[chromeno[4,3- acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (3-methoxy-4-tert-butyl- 1-3-methoxy-4-tert-butyl-benzoic phenyl)-(1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-isopentyloxyphenyl)-(1-1- 4-isopentyloxybenzoic acid methyl-1H- methylspiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-quinoline-8-carboxylic acid spiro[chromeno[4,3-methylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)(8-quinolyl)methanone[3-chloro-4-(2- 1- 3-chloro-4-(2- methoxyethoxy)phenyl]-(1-methylspiro[chromeno[4,3- methoxyethoxy)benzoic acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-isopropoxy-3-methyl- 1-4-isopropoxy-3-methyl-benzoic phenyl)-(1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-methoxy-3-methyl-phenyl)- 1- 2-methoxy-3-methyl-benzoic (1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (3-methoxy-4-propoxy- 1-3-methoxy-4-propoxy-benzoic phenyl)-(1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (2,3-dimethylphenyl)-(1- 1-2,3-dimethylbenzoic acid methyl-1H- methylspiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-isobutoxy-3-methoxy- 1-4-isobutoxy-3-methoxy- phenyl)-(1-methyl-1H- methylspiro[chromeno[4,3-benzoic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-isopentyloxy-3-methoxy-1- 4-isopentyloxy-3-methoxy- phenyl)-(1-methyl-1H-methylspiro[chromeno[4,3- benzoic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-chloro-3-methoxy-phenyl)- 1- 4-chloro-3-methoxy-benzoic (1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-4-(trifluoromethoxy)benzoic spiro[chromeno[4,3-methylspiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)[4-(trifluoromethoxy)phenyl]- methanone (3-fluoro-4-methoxy-phenyl)- 1-3-fluoro-4-methoxy-benzoic (1-methyl-1H- methylspiro[chromeno[4,3- acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(3-methoxy-4-methyl-phenyl)- 1- 3-methoxy-4-methyl-benzoic (1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (S)-(3-methoxy-4- 1-(S)-3-methoxy-4- (tetrahydrofuran-3- methylspiro[chromeno[4,3-(tetrahydrofuran-3- yloxy)phenyl)(1-methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride yloxy)benzoic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′- yl)methanone[3-methyl-4-(tetrahydrofuran- 1- 3-methyl-4-(tetrahydrofuran-2-2-ylmethoxy)phenyl]-(1- methylspiro[chromeno[4,3- ylmethoxy)benzoic acidmethyl-1H- c]pyrazole-4,4′-piperidine]dihydrochloridespiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′- yl)methanone(3-ethoxy-4-methoxy-phenyl)- 1- 3-ethoxy-4-methoxy-benzoic (1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (3,4-diethoxyphenyl)-(1- 1-3,4-diethoxybenzoic acid methyl-1H- methylspiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (3-fluoro-4-oxetan-3-yloxy-1- 3-fluoro-4-oxetan-3-yloxy- phenyl)-(1-methyl-1H-methylspiro[chromeno[4,3- benzoic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (3-fluoro-4-(oxetan-3- 1-2- yloxy)phenyl)(1-methyl-1H- methylspiro[chromeno[4,3-(methanesulfonamido)benzoic spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride acidc]pyrazole-4,4′-piperidine]-1′- yl)methanone (2-hydroxy-4-methoxy- 1-2-hydroxy-4-methoxy-benzoic phenyl)-(1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone methyl 2-(2-methoxy-4-(1-1- 3-methoxy-4-(1- methyl-1H- methylspiro[chromeno[4,3-methoxycarbonyl-1-methyl- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride ethyl)-benzoic acidc]pyrazole-4,4′-piperidine]-1′- ylcarbonyl)phenyl)-2- methylpropanoate(2,4-diisopropoxyphenyl)-(1- 1- 2,4-diisopropoxybenzoic acid methyl-1H-methylspiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(2,2-dimethyl-3H-benzofuran- 1- 2,2-dimethyl-3H-benzofuran-5-5-yl)-(1-methyl-1H- methylspiro[chromeno[4,3- carboxylic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(3,3-dimethyl-2H-benzofuran- 1- 3,3-dimethyl-2H-benzofuran-5-5-yl)-(1-methyl-1H- methylspiro[chromeno[4,3- carboxylic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone 1-isoquinolyl-(1-methyl-1H-1- isoquinoline-1-carboxylic acid spiro[chromeno[4,3-methylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)methanone (1-methyl-1H- 1-6-(1-piperidyl)pyridine-3- spiro[chromeno[4,3- methylspiro[chromeno[4,3-carboxylic acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochlorideyl)[6-(1-piperidyl)-3-pyridyl]- methanone (4-chloro-2-methylsulfonyl- 1-4-chloro-2-methylsulfonyl- phenyl)-(1-methyl-1H-methylspiro[chromeno[4,3- benzoic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-2-phenylthiazole-4-carboxylic spiro[chromeno[4,3-methylspiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)(2-phenylthiazol-4-yl)-methanone (5-chloro-2-methoxy-phenyl)- 1- 5-chloro-2-methoxy-benzoic(1-methyl-1H- methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-hydroxyphenyl)-(1-methyl- 1- 2-hydroxybenzoic acid1H-spiro[chromeno[4,3- methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)methanone(1-methylindol-2-yl)-(1- 1- 1-methylindole-2-carboxylic methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone[1-(4-fluorophenyl)-5-methyl- 1- 1-(4-fluorophenyl)-5-methyl-pyrazol-4-yl]-(1-methyl-1H- methylspiro[chromeno[4,3-pyrazole-4-carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (2,6-dimethoxyphenyl)-(1-1- 2,6-dimethoxybenzoic acid methyl-1H- methylspiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (2,5-dimethoxyphenyl)-(1-1- 2,5-dimethoxybenzoic acid methyl-1H- methylspiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(5-methyl-1-phenyl-pyrazol-4- 1- 5-methyl-1-phenyl-pyrazole-4-yl)-(1-methyl-1H- methylspiro[chromeno[4,3- carboxylic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-fluoro-6-methoxy-phenyl)- 1- 2-fluoro-6-methoxy-benzoic (1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-dimethylamino-4-pyridyl)- 1- 2-dimethylaminopyridine-4- (1-methyl-1H-methylspiro[chromeno[4,3- carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone [2-methyl-4- 1- 2-methyl-4-(trifluoromethoxy)phenyl]-(1- methylspiro[chromeno[4,3-(trifluoromethoxy)benzoic acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (2-methyl-1H-benzoimidazol-1- 2-methyl-1H-benzoimidazole- 4-yl)-(1-methyl-1H-methylspiro[chromeno[4,3- 4-carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-1-phenyl-5- spiro[chromeno[4,3- methylspiro[chromeno[4,3-(trifluoromethyl)pyrazole-4- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride carboxylic acidyl)[1-phenyl-5- (trifluoromethyl)pyrazol-4-yl]- methanone [2-methoxy-4-1- 2-methoxy-4- (trifluoromethoxy)phenyl]-(1- methylspiro[chromeno[4,3-(trifluoromethoxy)benzoic acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methylindol-5-yl)-(1- 1-1-methylindole-5-carboxylic methyl-1H- methylspiro[chromeno[4,3- acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-2-(1-piperidyl)pyridine-4- spiro[chromeno[4,3- methylspiro[chromeno[4,3-carboxylic acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochlorideyl)[2-(1-piperidyl)-4-pyridyl]- methanone (5-methoxy-1H-indol-3-yl)-(1-1- 5-methoxy-1H-indole-3- methyl-1H- methylspiro[chromeno[4,3-carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone [1-(4-methoxyphenyl)-5- 1-1-(4-methoxyphenyl)-5-methyl- methyl-pyrazol-4-yl]-(1-methylspiro[chromeno[4,3- pyrazole-4-carboxylic acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-methoxy-2-methyl-phenyl)- 1- 4-methoxy-2-methyl-benzoic (1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-methoxy-1H-indol-3-yl)-(1- 1- 4-methoxy-1H-indole-3- methyl-1H-methylspiro[chromeno[4,3- carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-chloro-4-methyl-phenyl)-(1- 1- 2-chloro-4-methyl-benzoic acidmethyl-1H- methylspiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(2,3-dimethyl-1H-indol-7-yl)- 1- 2,3-dimethyl-1H-indole-7- (1-methyl-1H-methylspiro[chromeno[4,3- carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone 1H-indol-4-yl-(1-methyl-1H-1- 1H-indole-4-carboxylic acid spiro[chromeno[4,3-methylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)methanone(5-fluoro-2-methoxy-phenyl)- 1- 5-fluoro-2-methoxy-benzoic (1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(7-methoxy-1H-indol-3-yl)-(1- 1- 7-methoxy-1H-indole-3- methyl-1H-methylspiro[chromeno[4,3- carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methylindol-3-yl)-(1- 1-1-methylindole-3-carboxylic methyl-1H- methylspiro[chromeno[4,3- acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (2-isopropoxy-5-methyl- 1-2-isopropoxy-5-methyl-benzoic phenyl)-(1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone2,5-dioxabicyclo[4.4.0]deca- 1- 2,5-dioxabicyclo[4.4.0]deca-6,8,10-trien-7-yl-(1-methyl- methylspiro[chromeno[4,3-6,8,10-triene-10-carboxylic 1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride acidc]pyrazole-4,4′-piperidine]-1′- yl)methanone(2,2-difluorobenzo[1,3]dioxol- 1- 2,2-difluorobenzo[1,3]dioxole-4-yl)-(1-methyl-1H- methylspiro[chromeno[4,3- 4-carboxylic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-methoxy-1-methyl-indol-3- 1- 4-methoxy-1-methyl-indole-3-yl)-(1-methyl-1H- methylspiro[chromeno[4,3- carboxylic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone [2-methoxy-4- 1-2-methoxy-4- (trifluoromethyl)phenyl]-(1- methylspiro[chromeno[4,3-(trifluoromethyl)benzoic acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-ethylphenyl)-(1-methyl-1H- 1- 2-ethylbenzoic acid spiro[chromeno[4,3-methylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)methanone[2-(difluoromethoxy)phenyl]- 1- 2-(difluoromethoxy)benzoic (1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (2,4-dimethoxyphenyl)-(1-1- 2,4-dimethoxybenzoic acid methyl-1H- methylspiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-methoxyphenyl)-(1-methyl- 1- 2-methoxybenzoic acid1H-spiro[chromeno[4,3- methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)methanone [4-methoxy-2- 1-4-methoxy-2- (trifluoromethoxy)phenyl]-(1- methylspiro[chromeno[4,3-(trifluoromethoxy)benzoic acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-isopropoxy-2-methoxy- 1-4-isopropoxy-2-methoxy- phenyl)-(1-methyl-1H- methylspiro[chromeno[4,3-benzoic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(2,2-dimethyl-3H-benzofuran- 1- 2,2-dimethyl-3H-benzofuran-7-7-yl)-(1-methyl-1H- methylspiro[chromeno[4,3- carboxylic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (3,5-difluorophenyl)-(1- 1-3,5-difluorobenzoic acid methyl-1H- methylspiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-chloro-2-methyl-phenyl)-(1- 1- 4-chloro-2-methyl-benzoic acidmethyl-1H- methylspiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone 1H-indol-7-yl-(1-methyl-1H-1- 1H-indole-7-carboxylic acid spiro[chromeno[4,3-methylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)methanone (1-methyl-1H- 1-5-(trifluoromethoxy)-1H- spiro[chromeno[4,3- methylspiro[chromeno[4,3-indole-2-carboxylic acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)[5-(trifluoromethoxy)-1H-indol-2-yl]-methanone [2-(3,5-dimethyl-1H-pyrazol- 1-2-(3,5-dimethyl-1H-pyrazol-4- 4-yl)phenyl]-(1-methyl-1H-methylspiro[chromeno[4,3- yl)benzoic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-2-phenyl-5- spiro[chromeno[4,3- methylspiro[chromeno[4,3-(trifluoromethyl)oxazole-4- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride carboxylic acidyl)[2-phenyl-5- (trifluoromethyl)oxazol-4-yl]- methanone[2-chloro-4-(2,5- 1- 2-chloro-4-(2,5-dimethylpyrrol-dimethylpyrrol-1-yl)-phenyl]- methylspiro[chromeno[4,3- 1-yl)-benzoicacid (1-methyl-1H- c]pyrazole-4,4′-piperidine]dihydrochloridespiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′- yl)methanone[4-chloro-2-[2-(2- 1- 4-chloro-2-[2-(2- thienyl)ethyl]phenyl]-(1-methylspiro[chromeno[4,3- thienyl)ethyl]benzoic acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-pyridazine-4-carboxylic acid spiro[chromeno[4,3-methylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)pyridazin-4-yl-methanone[4-hydroxy-7- 1- 4-hydroxy-7- (trifluoromethyl)-3-quinolyl]-methylspiro[chromeno[4,3- (trifluoromethyl)quinoline-3- (1-methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride carboxylic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′- yl)methanone(1-methyl-1H- 1- 6-phenoxypyridine-3- spiro[chromeno[4,3-methylspiro[chromeno[4,3- carboxylic acidc]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)(6-phenoxy-3-pyridyl)-methanone benzo[c]isoxazol-3-yl-(1- 1- benzo[c]isoxazole-3-carboxylicmethyl-1H- methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone [1-(4-fluorophenyl)-5- 1-1-(4-fluorophenyl)-5- (trifluoromethyl)pyrazol-4-yl]-methylspiro[chromeno[4,3- (trifluoromethyl)pyrazole-4- (1-methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride carboxylic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′- yl)methanone1,7-diazabicyclo[4.3.0]nona- 1- 1,7-diazabicyclo[4.3.0]nona-2,4,6,8-tetraen-8-yl-(1-methyl- methylspiro[chromeno[4,3-2,4,6,8-tetraene-8-carboxylic 1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride acidc]pyrazole-4,4′-piperidine]-1′- yl)methanone[3-(4-fluorophenyl)isoxazol-5- 1- 3-(4-fluorophenyl)isoxazole-5-yl]-(1-methyl-1H- methylspiro[chromeno[4,3- carboxylic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (3,5-diethoxyphenyl)-(1- 1-3,5-diethoxybenzoic acid methyl-1H- methylspiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-fluoro-2-methyl-phenyl)-(1- 1- 4-fluoro-2-methyl-benzoic acidmethyl-1H- methylspiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (7-methoxybenzofuran-2-yl)-1- 7-methoxybenzofuran-2- (1-methyl-1H- methylspiro[chromeno[4,3-carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-2-(4-pyridyl)thiazole-4- spiro[chromeno[4,3- methylspiro[chromeno[4,3-carboxylic acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochlorideyl)[2-(4-pyridyl)thiazol-4-yl]- methanone (1-methyl-1H- 1-5-phenylpyridine-3-carboxylic spiro[chromeno[4,3-methylspiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)(5-phenyl-3-pyridyl)-methanone (5-fluorobenzofuran-2-yl)-(1- 1- 5-fluorobenzofuran-2-methyl-1H- methylspiro[chromeno[4,3- carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (5-methoxybenzofuran-2-yl)-1- 5-methoxybenzofuran-2- (1-methyl-1H- methylspiro[chromeno[4,3-carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone [4-chloro-2-(2,5- 1-4-chloro-2-(2,5-dimethylpyrrol- dimethylpyrrol-1-yl)-phenyl]-methylspiro[chromeno[4,3- 1-yl)-benzoic acid (1-methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-3-phenylisoxazole-5-carboxylic spiro[chromeno[4,3-methylspiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)(3-phenylisoxazol-5-yl)-methanone (5-methylpyrazin-2-yl)-(1- 1- 5-methylpyrazine-2-carboxylicmethyl-1H- methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone1-(1-methylindol-3-yl)-2-(1- 1- 2-(1-methylindol-3-yl)-2-oxo- methyl-1H-methylspiro[chromeno[4,3- acetic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)ethane-1,2-dione (1-methyl-1H- 1-5-(m-tolyl)isoxazole-3- spiro[chromeno[4,3- methylspiro[chromeno[4,3-carboxylic acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochlorideyl)[5-(m-tolyl)isoxazol-3-yl]- methanone (3-chloro-1,7- 1- 3-chloro-1,7-diazabicyclo[4.3.0]nona- methylspiro[chromeno[4,3-diazabicyclo[4.3.0]nona- 2,4,6,8-tetraen-8-yl)-(1-c]pyrazole-4,4′-piperidine]dihydrochloride 2,4,6,8-tetraene-8-carboxylicmethyl-1H- acid spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-yl)methanone (1-methyl-1H- 1- 5-phenyl-1H-pyrazole-3-spiro[chromeno[4,3- methylspiro[chromeno[4,3- carboxylic acidc]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochlorideyl)(5-phenyl-1H-pyrazol-3-yl)- methanone [2-(4-chlorophenyl)thiazol-4-1- 2-(4-chlorophenyl)thiazole-4- yl]-(1-methyl-1H-methylspiro[chromeno[4,3- carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone[2-(4-chlorophenyl)-4-methyl- 1- 2-(4-chlorophenyl)-4-methyl-thiazol-5-yl]-(1-methyl-1H- methylspiro[chromeno[4,3-thiazole-5-carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-5-phenylisoxazole-3-carboxylic spiro[chromeno[4,3-methylspiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)(5-phenylisoxazol-3-yl)-methanone (1-methyl-1H- 1- 5-phenyloxazole-4-carboxylicspiro[chromeno[4,3- methylspiro[chromeno[4,3- acidc]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)(5-phenyloxazol-4-yl)-methanone (1-methyl-1H- 1- 2-(p-tolyl)thiazole-4-carboxylicspiro[chromeno[4,3- methylspiro[chromeno[4,3- acidc]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)[2-(p-tolyl)thiazol-4-yl]-methanone [5-(4-fluorophenyl)isoxazol-3- 1-5-(4-fluorophenyl)isoxazole-3- yl]-(1-methyl-1H-methylspiro[chromeno[4,3- carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-fluoro-4-methoxy-phenyl)- 1- 2-fluoro-4-methoxy-benzoic (1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-methoxy-2-quinolyl)-(1-1- 4-methoxyquinoline-2- methyl-1H- methylspiro[chromeno[4,3- carboxylicacid spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(3,5-ditert-butylphenyl)-(1- 1- 3,5-ditert-butylbenzoic acid methyl-1H-methylspiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (2-chloro-4-methylsulfonyl-1- 2-chloro-4-methylsulfonyl- phenyl)-(1-methyl-1H-methylspiro[chromeno[4,3- benzoic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-5-(2-pyridyl)thiophene-2- spiro[chromeno[4,3- methylspiro[chromeno[4,3-carboxylic acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)[5-(2-pyridyl)-2-thienyl]-methanone tert-butyl 5-chloro-2-(1- 1- 4-chloro-2-(tert- methyl-1H-methylspiro[chromeno[4,3- butoxycarbonylamino)-benzoicspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloride acidc]pyrazole-4,4′-piperidine]-1′- ylcarbonyl)phenylcarbamate[5-(4-methoxyphenyl)isoxazol- 1- 5-(4-methoxyphenyl)isoxazole-3-yl]-(1-methyl-1H- methylspiro[chromeno[4,3- 3-carboxylic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone [3,5- 1-3,5-bis(trifluoromethyl)benzoic bis(trifluoromethyl)phenyl]-(1-methylspiro[chromeno[4,3- acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone [5-methyl-1-[3- 1-5-methyl-1-[3- (trifluoromethyl)phenyl]-1,2,4- methylspiro[chromeno[4,3-(trifluoromethyl)phenyl]-1,2,4- triazol-3-yl]-(1-methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride triazole-3-carboxylic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′- yl)methanone[2-[(4-chlorophenyl)methyl]-5- 1- 2-[(4-chlorophenyl)methyl]-5-methyl-pyrazol-3-yl]-(1- methylspiro[chromeno[4,3-methyl-pyrazole-3-carboxylic methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone(7-ethoxybenzofuran-2-yl)-(1- 1- 7-ethoxybenzofuran-2- methyl-1H-methylspiro[chromeno[4,3- carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone [1-(2,4-dichlorophenyl)-5-1- 1-(2,4-dichlorophenyl)-5- methyl-1,2,4-triazol-3-yl]-(1-methylspiro[chromeno[4,3- methyl-1,2,4-triazole-3- methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride carboxylic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′- yl)methanone1-methyl-3- 1- 1-methyl-4-oxo-quinoline-3- (methylBLAHyl)carbonyl-methylspiro[chromeno[4,3- carboxylic acid quinolin-4-onec]pyrazole-4,4′-piperidine]dihydrochloride 8-isoquinolyl-(1-methyl-1H-1- isoquinoline-8-carboxylic acid spiro[chromeno[4,3-methylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)methanone[2-(2,3-dihydrobenzofuran-5- 1- 2-(2,3-dihydrobenzofuran-5-yl)thiazol-4-yl]-(1-methyl-1H- methylspiro[chromeno[4,3-yl)thiazole-4-carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-methoxy-4-methyl-phenyl)- 1- 2-methoxy-4-methyl-benzoic (1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (3,5-dimethylphenyl)-(1- 1-3,5-dimethylbenzoic acid methyl-1H- methylspiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-methyloxazol-5-yl)-(1-1- 4-methyloxazole-5-carboxylic methyl-1H- methylspiro[chromeno[4,3-acid spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone [4-methoxy-2- 1-4-methoxy-2- (trifluoromethyl)phenyl]-(1- methylspiro[chromeno[4,3-(trifluoromethyl)benzoic acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone [2-(4-fluorophenoxy)-3- 1-2-(4-fluorophenoxy)pyridine-3- pyridyl]-(1-methyl-1H-methylspiro[chromeno[4,3- carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-benzyloxy-2-chloro- 1-4-benzyloxy-2-chloro-benzoic phenyl)-(1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-2-phenoxypyridine-3- spiro[chromeno[4,3- methylspiro[chromeno[4,3-carboxylic acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)(2-phenoxy-3-pyridyl)-methanone [2-(2-chloro-1,1,2-trifluoro- 1- 2-(2-chloro-1,1,2-trifluoro-ethoxy)-4-methoxy-phenyl]-(1- methylspiro[chromeno[4,3-ethoxy)-4-methoxy-benzoic methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone 2,3-dihydrobenzofuran-7-yl-1- 2,3-dihydrobenzofuran-7- (1-methyl-1H- methylspiro[chromeno[4,3-carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone [3-chloro-5- 1- 3-chloro-5-(trifluoromethyl)phenyl]-(1- methylspiro[chromeno[4,3-(trifluoromethyl)benzoic acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone[3-(4-chlorophenyl)isoxazol-5- 1- 3-(4-chlorophenyl)isoxazole-5-yl]-(1-methyl-1H- methylspiro[chromeno[4,3- carboxylic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-benzylindol-3-yl)-(1- 1-1-benzylindole-3-carboxylic methyl-1H- methylspiro[chromeno[4,3- acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone1,7-diazabicyclo[4.3.0]nona- 1- 1,7-diazabicyclo[4.3.0]nona-2,4,6,8-tetraen-5-yl-(1-methyl- methylspiro[chromeno[4,3-2,4,6,8-tetraene-5-carboxylic 1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride acidc]pyrazole-4,4′-piperidine]-1′- yl)methanone5-isopropoxy-2-(1-methyl-1H- 1- 2-cyano-4-isopropoxy-benzoicspiro[chromeno[4,3- methylspiro[chromeno[4,3- acidc]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride ylcarbonyl)benzonitrile(2-chloro-4-isopropoxy- 1- 2-chloro-4-isopropoxy-benzoicphenyl)-(1-methyl-1H- methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-isopropoxy-2-methyl- 1-4-isopropoxy-2-methyl-benzoic phenyl)-(1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (2-fluoro-4-isopropoxy- 1-2-fluoro-4-isopropoxy-benzoic phenyl)-(1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (2-isopropoxy-3-methyl- 1-2-isopropoxy-3-methyl-benzoic phenyl)-(1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone2-(2-methoxy-4-(1-methyl-1H- 1- 4-(1-cyano-1-methyl-ethoxy)-spiro[chromeno[4,3- methylspiro[chromeno[4,3- 3-methoxy-benzoic acidc]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride ylcarbonyl)phenoxy)-2-methylpropanenitrile [3-chloro-4- 1- 3-chloro-4-(trifluoromethoxy)phenyl]-(1- methylspiro[chromeno[4,3-(trifluoromethoxy)benzoic acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-isopropoxy-3-methoxy- 1-4-isopropoxy-3-methoxy- phenyl)-(1-methyl-1H- methylspiro[chromeno[4,3-benzoic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-hydroxy-3-methyl-phenyl)- 1- 4-hydroxy-3-methyl-benzoic (1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (3-fluoro-4-isopropoxy- 1-3-fluoro-4-isopropoxy-benzoic phenyl)-(1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (3-methyl-4-tert-butoxy- 1-3-methyl-4-tert-butoxy-benzoic phenyl)-(1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (3-chloro-4-isopropoxy- 1-3-chloro-4-isopropoxy-benzoic phenyl)-(1-methyl-1H-methylspiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)methanone (7-chloro-1-methyl-1H-7-chloro-1-methyl-1H- 4-isopropoxy-3-methylbenzoic spiro[chromeno[4,3-spiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)(4-isopropoxy-3- methylphenyl)methanone(8-chloro-1-methyl-1H- 8-chloro-1-methyl-1H-4-isopropoxy-3-methylbenzoic spiro[chromeno[4,3- spiro[chromeno[4,3-acid c]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine]yl)(4-isopropoxy-3- methylphenyl)methanone (4-isopropoxy-3-8-methoxy-1-methyl-1H- 4-isopropoxy-3-methylbenzoicmethylphenyl)(8-methoxy-1- spiro[chromeno[4,3- acid methyl-1H-c]pyrazole-4,4′-piperidine] spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1,3-dimethyl-1H-1,3-dimethyl-1H- 4-isopropoxy-3-methylbenzoic spiro[chromeno[4,3-spiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine]dihydrochloride yl)(4-isopropoxy-3-methylphenyl)methanone (4-isopropoxy-3- 1H-Spiro[chromeno[4,3-4-isopropoxy-3-methylbenzoic methylphenyl)(1H-c]pyrazole-4,4′-piperidine] acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-ethyl-1H- 1-ethyl-1H-3-methoxy-4-(2- spiro[chromeno[4,3- spiro[chromeno[4,3-methoxyethoxy)benzoic acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)(3-methoxy-4-(2-methoxyethoxy)phenyl)methanone (1-ethyl-1H- 1-ethyl-1H-4-isopropoxy-3-methylbenzoic spiro[chromeno[4,3- spiro[chromeno[4,3-acid c]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine]yl)(4-isopropoxy-3- methylphenyl)methanone (1-ethyl-1H- 1-ethyl-1H-4-(isopentyloxy)-3- spiro[chromeno[4,3- spiro[chromeno[4,3-methoxybenzoic acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)(4-(isopentyloxy)-3-methoxyphenyl)methanone (4-tert-butyl-3- 1-ethyl-1H-4-tert-butyl-3-methoxybenzoic methoxyphenyl)(1-ethyl-1H-spiro[chromeno[4,3- acid spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone (3-methoxy-4-(2-1-(2-methoxyethyl)-1H- 3-methoxy-4-(2- methoxyethoxy)phenyl)(1-(2-spiro[chromeno[4,3- methoxyethoxy)benzoic acid methoxyethyl)-1H-c]pyrazole-4,4′-piperidine]hydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-tert-butyl-3-1-(2-methoxyethyl)-1H- 4-tert-butyl-3-methoxybenzoicmethoxyphenyl)(1-(2- spiro[chromeno[4,3- acid methoxyethyl)-1H-c]pyrazole-4,4′-piperidine]hydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-(isopentyloxy)-3-1-(2-methoxyethyl)-1H- 4-(isopentyloxy)-3- methoxyphenyl)(1-(2-spiro[chromeno[4,3- methoxybenzoic acid methoxyethyl)-1H-c]pyrazole-4,4′-piperidine]hydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone 3-methoxy-4-(2-1-(2,2,2-trifluoroethyl)-1H- 3-methoxy-4-(2- methoxyethoxy)phenyl)(1-spiro[chromeno[4,3- methoxyethoxy)benzoic acid(2,2,2-trifluoroethyl)-1H- c]pyrazole-4,4′-piperidine]spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-(isopentyloxy)-3- 1-(2,2,2-trifluoroethyl)-1H- 4-(isopentyloxy)-3-methoxyphenyl)(1-(2,2,2- spiro[chromeno[4,3- methoxybenzoic acidtrifluoroethyl)-1H- c]pyrazole-4,4′-piperidine] spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-(isopentyloxy)-3-2-(2,2,2-trifluoroethyl)-2H- 4-(isopentyloxy)-3-methoxyphenyl)(2-(2,2,2- spiro[chromeno[4,3- methoxybenzoic acidtrifluoroethyl)-2H- c]pyrazole-4,4′-piperidine] spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1- 1- Benzoic acidmethylspiro[benzo[b]pyrrolo[1, methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]-1′-piperidine] yl)(phenyl)methanone (4-ethyl-3-methoxyphenyl)(1- 1-4-ethyl-3-methoxybenzoic acid methylspiro[benzo[b]pyrrolo[1,methylspiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone piperidine](4-ethyl-3-methoxyphenyl)(2- 2- 4-ethyl-3-methoxybenzoic acidmethylspiro[benzo[b]pyrrolo[1, methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone piperidine] (4-ethyl-3-methoxyphenyl)(3- 3-4-ethyl-3-methoxybenzoic acid methylspiro[benzo[b]pyrrolo[1,methylspiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)methanone piperidine](4-isopropoxy-3- 1- 4-isopropoxy-3-methylbenzoic methylphenyl)(1-methylspiro[benzo[b]pyrrolo[1, acid methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (4-isopropoxy-3- 2-4-isopropoxy-3-methylbenzoic methylphenyl)(2-methylspiro[benzo[b]pyrrolo[1, acid methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (4-isopropoxy-3- 3-4-isopropoxy-3-methylbenzoic methylphenyl)(3-methylspiro[benzo[b]pyrrolo[1, acid methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (4-methoxy-3- 1- 4-methoxy-3-(trifluoromethyl)phenyl)(1- methylspiro[benzo[b]pyrrolo[1,(trifluoromethyl)benzoic acid methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (4-methoxy-3- 2- 4-methoxy-3-(trifluoromethyl)phenyl)(2- methylspiro[benzo[b]pyrrolo[1,(trifluoromethyl)benzoic acid methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (4-methoxy-3- 3- 4-methoxy-3-(trifluoromethyl)phenyl)(3- methylspiro[benzo[b]pyrrolo[1,(trifluoromethyl)benzoic acid methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (3-methoxy-4-(2- 1- 3-methoxy-4-(2-methoxyethoxy)phenyl)(1- methylspiro[benzo[b]pyrrolo[1,methoxyethoxy)benzoic acid methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′- 2-d][1,4]oxazine-4,4′- piperidine]piperidine]-1′-yl)methanone (1- 1- 4-propoxy-3-methylspiro[benzo[b]pyrrolo[1, methylspiro[benzo[b]pyrrolo[1,(trifluoromethyl)benzoic acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(4-propoxy-3- piperidine](trifluoromethyl)phenyl)methanone (4-ethyl-3-methoxyphenyl)(1- 1-4-ethyl-3-methoxybenzoic acid (trifluoromethyl)spiro[benzo[b]pyrrolo[1,(trifluoromethyl)spiro[benzo[b]pyrrolo[1, 2-d][1,4]oxazine- 2-4,4′-piperidine]-1′- d][1,4]oxazine-4,4′- yl)methanone piperidine](3-methoxy-4-(2- 1- 3-methoxy-4-(2- methoxyethoxy)phenyl)(1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1, methoxyethoxy)benzoic acid(trifluoromethyl)spiro[benzo[b]pyrrolo[1, 2- 2-d][1,4]oxazine-d][1,4]oxazine-4,4′- 4,4′-piperidine]-1′- piperidine] yl)methanone(4-propoxy-3- spiro[piperidine-4,6′- 4-propoxy-3-(trifluoromethyl)phenyl)(spiro[piperidine- pyrido[3,2-b]pyrrolo[1,2-(trifluoromethyl)benzoic acid 4,6′-pyrido[3,2- d][1,4]oxazine]b]pyrrolo[1,2-d][1,4]oxazine]- 1-yl)methanone (4-(isopentyloxy)-3-spiro[piperidine-4,6′- 4-(isopentyloxy)-3-methoxyphenyl)(spiro[piperidine- pyrido[3,2-b]pyrrolo[1,2-methoxybenzoic acid 4,6′-pyrido[3,2- d][1,4]oxazine]b]pyrrolo[1,2-d][1,4]oxazine]- 1-yl)methanone (4-tert-butyl-3-spiro[piperidine-4,6′- 4-tert-butyl-3-methoxybenzoicmethoxyphenyl)(spiro[piperidine- pyrido[3,2-b]pyrrolo[1,2- acid4,6′-pyrido[3,2- d][1,4]oxazine] b]pyrrolo[1,2-d][1,4]oxazine]-1-yl)methanone (R)-(3-methoxy-4- spiro[piperidine-4,6′- (R)-3-methoxy-4-(tetrahydrofuran-3- pyrido[3,2-b]pyrrolo[1,2- (tetrahydrofuran-3-yloxy)phenyl)(spiro[piperidine- d][1,4]oxazine] yloxy)benzoic acid4,6′-pyrido[3,2-b]pyrrolo[1,2- d][1,4]oxazine]-1- yl)methanone(3-methoxy-4-(2- spiro[piperidine-4,6′- 3-methoxy-4-(2-methoxyethoxy)phenyl)(spiro[piperidine- pyrido[3,2-b]pyrrolo[1,2-methoxyethoxy)benzoic acid 4,6′-pyrido[3,2- d][1,4]oxazine]b]pyrrolo[1,2-d][1,4]oxazine]- 1-yl)methanone(4-ethyl-3-methoxyphenyl)(2- 2- 4-ethyl-3-methoxybenzoic acidmethylspiro[chromeno[3,4- methylspiro[chromeno[3,4-d]thiazole-4,4′-piperidine]-1′- d]thiazole-4,4′-piperidine] yl)methanone(4-methoxy-3- 1-methyl-1H- 4-methoxy-3- (trifluoromethyl)phenyl)(1-spiro[chromeno[4,3- (trifluoromethyl)benzoic acid methyl-1H-b]pyrrole-4,4′-piperidine] spiro[chromeno[4,3-b]pyrrole-4,4′-piperidine]-1′- yl)methanone (3-methoxy-4-(2- spiro[chromeno[4,3-3-methoxy-4-(2- methoxyethoxy)phenyl)(1- b]pyrrole-4,4′-piperidine]methoxyethoxy)benzoic acid methyl-1H- spiro[chromeno[4,3-b]pyrrole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-methyl-1H-3-(methylsulfonyl)benzoic acid spiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine] yl)(3-(methylsulfonyl)phenyl)methanone (4-chlorophenyl)(1-methyl-1H-1-methyl-1H- 4-chlorobenzoic acid spiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)methanone (2-methoxypyridin-3-yl)(1-1-methyl-1H- 2-methoxynicotinic acid methyl-1H- spiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-methyl-1H-quinoline-2-carboxylic acid spiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine]yl)(quinolin-2-yl)methanone (3-(2-chlorophenyl)isoxazol-5- 1-methyl-1H-3-(2-chlorophenyl)isoxazole-5- yl)(1-methyl-1H- spiro[chromeno[4,3-carboxylic acid spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-methyl-1H-2-(trifluoromethyl)-1,8- spiro[chromeno[4,3- spiro[chromeno[4,3-naphthyridine-3-carboxylic c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] acid yl)(2-(trifluoromethyl)-1,8-naphthyridin-3-yl)methanone (2,4-dimethylphenyl)(1- 1-methyl-1H-2,4-dimethylbenzoic acid methyl-1H- spiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone (2-methoxy-5- 1-methyl-1H-2-methoxy-5-methylbenzoic methylphenyl)(1-methyl-1H- spiro[chromeno[4,3-acid spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-tert-butoxy-3-1H-spiro[chromeno[4,3- 4-tert-butoxy-3- methoxyphenyl)(1H-c]pyrazole-4,4′-piperidine] methoxybenzoic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (2,3-dimethoxyphenyl)(1-1-methyl-1H- 2,3-dimethoxybenzoic acid methyl-1H- spiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone(3-fluoro-2-methoxyphenyl)(1- 1-methyl-1H- 3-fluoro-2-methoxybenzoicmethyl-1H- spiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-methoxy-6- 1-methyl-1H- 2-methoxy-6-methylbenzoicmethylphenyl)(1-methyl-1H- spiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(2,3-dihydrobenzofuran-4- 1-methyl-1H- 2,3-dihydrobenzofuran-4-yl)(1-methyl-1H- spiro[chromeno[4,3- carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanonechroman-8-yl(1-methyl-1H- 1-methyl-1H- chroman-8-carboxylic acidspiro[chromeno[4,3- spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)methanone (3,4-dihydro-2H- 1-methyl-1H-3,4-dihydro-2H- benzo[b][1,4]dioxepin-6-yl)(1- spiro[chromeno[4,3-benzo[b][1,4]dioxepine-6- methyl-1H- c]pyrazole-4,4′-piperidine]carboxylic acid spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-yl)methanone (3-chloro-2-methoxyphenyl)(1- 1-methyl-1H-3-chloro-2-methoxybenzoic methyl-1H- spiro[chromeno[4,3- acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-chloro-6-methoxyphenyl)(1- 1-methyl-1H- 2-chloro-6-methoxybenzoicmethyl-1H- spiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(4,5-difluoro-2- 1-methyl-1H- 4,5-difluoro-2-methoxybenzoicmethoxyphenyl)(1-methyl-1H- spiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-ethoxyphenyl)(1-methyl- 1-methyl-1H- 2-ethoxybenzoic acid1H-spiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine] yl)methanone(2-isopropoxyphenyl)(1- 1-methyl-1H- 2-isopropoxybenzoic acid methyl-1H-spiro[chromeno[4,3- spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone (3-methoxypyridin-4-yl)(1-1-methyl-1H- 3-methoxyisonicotinic acid methyl-1H- spiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-methyl-1H-3-methyl-4- spiro[chromeno[4,3- spiro[chromeno[4,3-(trifluoromethoxy)benzoic acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)(3-methyl-4-(trifluoromethoxy)phenyl)methanone (2-hydroxy-3- 1-methyl-1H-2-hydroxy-3-isopropylbenzoic isopropylphenyl)(1-methyl-spiro[chromeno[4,3- acid 1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-methoxy-3,5- 1-methyl-1H- 4-methoxy-3,5- dimethylphenyl)(1-methyl-1H-spiro[chromeno[4,3- dimethylbenzoic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(1-methyl-1H- 1-methyl-1H- 4- spiro[chromeno[4,3- spiro[chromeno[4,3-(trifluoromethylsulfonyl)benzoic c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] acid yl)(4-(trifluoromethylsulfonyl)phenyl)methanone (4- 1-methyl-1H- 4-(difluoromethylsulfonyl)phenyl)(1- spiro[chromeno[4,3-(difluoromethylsulfonyl)benzoic methyl-1H- c]pyrazole-4,4′-piperidine]acid spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-isopropoxy-3,5- 1-methyl-1H- 4-isopropoxy-3,5-dimethylphenyl)(1-methyl-1H- spiro[chromeno[4,3- dimethylbenzoic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-methyl-1H-2-methylbenzo[d]oxazole-7- spiro[chromeno[4,3- spiro[chromeno[4,3-carboxylic acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)(2-methylbenzo[d]oxazol-7- yl)methanone(4-fluoro-2-methoxyphenyl)(1- 1-methyl-1H- 4-fluoro-2-methoxybenzoicmethyl-1H- spiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(8-methoxy-1-methyl-1H- 8-methoxy-1-methyl-1H- 2-methoxybenzoic acidspiro[chromeno[4,3- spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)(2- methoxyphenyl)methanone (2-8-methoxy-1-methyl-1H- 2-(difluoromethoxy)benzoic(difluoromethoxy)phenyl)(8- spiro[chromeno[4,3- acidmethoxy-1-methyl-1H- c]pyrazole-4,4′-piperidine] spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-chlorophenyl)(1-methyl-1H- 1-methyl-1H- 2-chlorobenzoic acidspiro[chromeno[4,3- spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)methanone (2-(2- 1-methyl-1H-2-(2-hydroxyethoxy)benzoic hydroxyethoxy)phenyl)(1- spiro[chromeno[4,3-acid methyl-1H- c]pyrazole-4,4′-piperidine] spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-methyl-1H-2-(tetrahydro-2H-pyran-4- spiro[chromeno[4,3- spiro[chromeno[4,3-yloxy)benzoic acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)(2-(tetrahydro-2H-pyran-4-yloxy)phenyl)methanone (1-methyl-1H- 1-methyl-1H- 2-(methylthio)benzoicacid spiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine] yl)(2-(methylthio)phenyl)methanone (2,3-dimethyl-2,3- 1-methyl-1H-2,3-dimethyl-2,3- dihydrobenzofuran-7-yl)(1- spiro[chromeno[4,3-dihydrobenzofuran-7- methyl-1H- c]pyrazole-4,4′-piperidine] carboxylicacid spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-fluoro-2-methylphenyl)(1- 1-methyl-1H- 4-fluoro-2-methylbenzoic acidmethyl-1H- spiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(5-isopropoxyquinolin-8-yl)(1- 1-methyl-1H- 5-isopropoxyquinoline-8-methyl-1H- spiro[chromeno[4,3- carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-bromo-3-methylphenyl)(1- 1-methyl-1H- 4-bromo-3-methylbenzoic acidmethyl-1H- spiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-bromo-3- 1-methyl-1H- 4-bromo-3-methoxybenzoicmethoxyphenyl)(1-methyl-1H- spiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-tert-butoxy-2- 1-methyl-1H- 4-tert-butoxy-2-methoxyphenyl)(1-methyl-1H- spiro[chromeno[4,3- methoxybenzoic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H-pyrrolo[3,2-1-methyl-1H- 1-methyl-1H-pyrrolo[3,2- b]pyridin-3-yl)(1-methyl-1H-spiro[chromeno[4,3- b]pyridine-3-carboxylic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone2-(3-methoxy-4-(1-methyl-1H- 1-methyl-1H- 4-(2-cyanopropan-2-yloxy)-2-spiro[chromeno[4,3- spiro[chromeno[4,3- methoxybenzoic acidc]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine]ylcarbonyl)phenoxy)-2- methylpropanenitrile (4-tert-butoxy-2-1-methyl-1H- 4-tert-butoxy-2-fluorobenzoic fluorophenyl)(1-methyl-1H-spiro[chromeno[4,3- acid spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H- 1-methyl-1H-2-methylbenzoic acid spiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine]yl)(o-tolyl)methanone (3-fluoro-2-methylphenyl)(1- 1-methyl-1H-3-fluoro-2-methylbenzoic acid methyl-1H- spiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone(2,3-difluorophenyl)(1-methyl- 1-methyl-1H- 2,3-difluorobenzoic acid1H-spiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine] yl)methanone(2-(methoxymethyl)phenyl)(1- 1-methyl-1H- 2-(methoxymethyl)benzoic acidmethyl-1H- spiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(3,4-difluoro-2- 1-methyl-1H- 3,4-difluoro-2-methoxybenzoicmethoxyphenyl)(1-methyl-1H- spiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(2,3-difluoro-6- 1-methyl-1H- 2,3-difluoro-6-methoxybenzoicmethoxyphenyl)(1-methyl-1H- spiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-(isobutylsulfonyl)phenyl)(1- 1-methyl-1H- 4-(isobutylsulfonyl)benzoicmethyl-1H- spiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-isopropoxy-2,5- 1-methyl-1H- 4-isopropoxy-2,5-dimethylphenyl)(1-methyl-1H- spiro[chromeno[4,3- dimethylbenzoic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone(3-ethoxy-2-fluorophenyl)(1- 1-methyl-1H- 3-ethoxy-2-fluorobenzoic acidmethyl-1H- spiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(8-fluoro-1-methyl-1H- 8-fluoro-1-methyl-1H- 2-methoxybenzoic acidspiro[chromeno[4,3- spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)(2- methoxyphenyl)methanone(1-ethyl-8-fluoro-1H- 1-ethyl-8-fluoro-1H- 2-methoxybenzoic acidspiro[chromeno[4,3- spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)(2- methoxyphenyl)methanone(2-(difluoromethyl)phenyl)(8- 8-fluoro-1-methyl-1H-2-(difluoromethyl)benzoic acid fluoro-1-methyl-1H- spiro[chromeno[4,3-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone (8-fluoro-1-methyl-1H-8-fluoro-1-methyl-1H- 2-(trifluoromethoxy)benzoic spiro[chromeno[4,3-spiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)(2- (trifluoromethoxy)phenyl)methanone(7-chloro-1-methyl-1H- 7-chloro-1-methyl-1H- 3-fluoro-2-methoxybenzoicspiro[chromeno[4,3- spiro[chromeno[4,3- acidc]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine]yl)(3-fluoro-2- methoxyphenyl)methanone (7-chloro-1-methyl-1H-7-chloro-1-methyl-1H- 2-(difluoromethoxy)-3- spiro[chromeno[4,3-spiro[chromeno[4,3- fluorobenzoic acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)(2-(difluoromethoxy)-3-fluorophenyl)methanone (2-(difluoromethoxy)-3- 1-methyl-1H-2-(difluoromethoxy)-3- fluorophenyl)(1-methyl-1H- spiro[chromeno[4,3-fluorobenzoic acid spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone N-methyl-4-(1-methyl-1H-1-methyl-1H- 4-(N-methylsulfamoyl)benzoic spiro[chromeno[4,3-spiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] ylcarbonyl)benzenesulfonamideN-ethyl-4-(1-methyl-1H- 1-methyl-1H- 4-(N-ethylsulfamoyl)benzoicspiro[chromeno[4,3- spiro[chromeno[4,3- acidc]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine]ylcarbonyl)benzenesulfonamide N,N-dimethyl-4-(1-methyl-1H- 1-methyl-1H-4-(N,N- spiro[chromeno[4,3- spiro[chromeno[4,3-dimethylsulfamoyl)benzoic c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] acid ylcarbonyl)benzenesulfonamide(3-fluoro-2-methoxyphenyl)(1- 1-isopropyl-1H- 3-fluoro-2-methoxybenzoicisopropyl-1H- spiro[chromeno[4,3- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(2- 1-isopropyl-1H- 2-(difluoromethoxy)benzoic(difluoromethoxy)phenyl)(1- spiro[chromeno[4,3- acid isopropyl-1H-c]pyrazole-4,4′-piperidine] spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-isopropyl-1H-1-isopropyl-1H- 4-(isopropylsulfonyl)benzoic spiro[chromeno[4,3-spiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)(4- (isopropylsulfonyl)phenyl)methanone(2- 8-fluoro-1-methyl-1H- 2-(difluoromethoxy)benzoic(difluoromethoxy)phenyl)(8- spiro[chromeno[4,3- acid fluoro-1-methyl-1H-c]pyrazole-4,4′-piperidine] spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (2- 1-ethyl-8-fluoro-1H-2-(difluoromethoxy)benzoic (difluoromethoxy)phenyl)(1-spiro[chromeno[4,3- acid ethyl-8-fluoro-1H- c]pyrazole-4,4′-piperidine]spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′- yl)methanone(1-ethyl-1H- 1-ethyl-1H- 3-methyl-4- spiro[chromeno[4,3-spiro[chromeno[4,3- (methylsulfonyl)benzoic acidc]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine]yl)(3-methyl-4- (methylsulfonyl)phenyl)methanone (1-ethyl-8-fluoro-1H-1-ethyl-8-fluoro-1H- 4-isopropoxy-3- spiro[chromeno[4,3-spiro[chromeno[4,3- methoxybenzoic acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)(4-isopropoxy-3- methoxyphenyl)methanone(1-ethyl-8-fluoro-1H- 1-ethyl-8-fluoro-1H- 4-isopropoxy-3-methylbenzoicspiro[chromeno[4,3- spiro[chromeno[4,3- acidc]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine]yl)(4-isopropoxy-3- methylphenyl)methanone (4-isopropoxy-3-spiro[piperidine-4,4′- 4-isopropoxy-3-methylbenzoicmethylphenyl)(spiro[piperidine- pyrazolo[1,5-d]pyrido[2,3- acid4,4′-pyrazolo[1,5- b][1,4]oxazine] d]pyrido[2,3-b][1,4]oxazine]-1-yl)methanone [1′- 1′- 2,3,4-trimethoxybenzoic acid(trifluoromethyl)spiro[piperidine- (trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1-yl]-(2,3,4-c][1,4]benzoxazine] trimethoxyphenyl)methanone(2-methylspiro[chromeno[4,3- 2-methylspiro[chromeno[4,3-3,4,5-trimethoxybenzoic acid c]pyrazole-4,4′-piperidine]-1′-yl)-c]pyrazole-4,4′-piperidine] (3,4,5- trimethoxyphenyl)methanone(2-methylspiro[chromeno[4,3- 2-methylspiro[chromeno[4,3-2,4,5-trimethoxybenzoic acid c]pyrazole-4,4′-piperidine]-1′-yl)-c]pyrazole-4,4′-piperidine] (2,4,5- trimethoxyphenyl)methanone(2-methylspiro[chromeno[4,3- 2-methylspiro[chromeno[4,3-2,3,4-trimethoxybenzoic acid c]pyrazole-4,4′-piperidine]-1′-yl)-c]pyrazole-4,4′-piperidine] (2,3,4- trimethoxyphenyl)methanone(1-methylspiro[chromeno[4,3- 1-methylspiro[chromeno[4,3-2,3,4-trimethoxybenzoic acid c]pyrazole-4,4′-piperidine]-1′-yl)-c]pyrazole-4,4′-piperidine] (2,3,4- trimethoxyphenyl)methanone(2-amino-1,3-benzothiazol-6-yl)- 1′- 2-amino-1,3-benzothiazole-6- [1′-(trifluoromethyl)spiro[piperidine- carboxylic acid(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl]methanone(2-amino-1,3-benzothiazol-6-yl)- 2-methylspiro[chromeno[4,3-2-amino-1,3-benzothiazole-6- (2-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] carboxylic acidc]pyrazole-4,4′-piperidine]-1′- yl)methanone 1H-indazol-5-yl-[1′- 1′-1H-indazole-5-carboxylic acid (trifluoromethyl)spiro[piperidine-(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1- c][1,4]benzoxazine] yl]methanone1H-indazol-5-yl-(1- 1-methylspiro[chromeno[4,3- 1H-indazole-5-carboxylicacid methylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone 1H-indazol-5-yl-(2-2-methylspiro[chromeno[4,3- 1H-indazole-5-carboxylic acidmethylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone[4-(difluoromethoxy)phenyl]-[1′- 1′- 4-(difluoromethoxy)benzoic acid(trifluoromethyl)spiro[piperidine- (trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1-c][1,4]benzoxazine] yl]methanone [4-(difluoromethoxy)phenyl]-(1-1-methylspiro[chromeno[4,3- 4-(difluoromethoxy)benzoic acidmethylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone[4-(difluoromethoxy)phenyl]-(2- 2-methylspiro[chromeno[4,3-4-(difluoromethoxy)benzoic acid methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-amino-1,3-benzothiazol-6-yl)- 1-methylspiro[chromeno[4,3-2-amino-1,3-benzothiazole-6- (1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] carboxylic acidc]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-chloro-1,3-benzothiazol-6-yl)- 1′- 2-chloro-1,3-benzothiazole-6- [1′-(trifluoromethyl)spiro[piperidine- carboxylic acid(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl]methanone(2-chloro-1,3-benzothiazol-6-yl)- 1-methylspiro[chromeno[4,3-2-chloro-1,3-benzothiazole-6- (1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] carboxylic acidc]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-chloro-1,3-benzothiazol-6-yl)- 2-methylspiro[chromeno[4,3-2-chloro-1,3-benzothiazole-6- (2-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] carboxylic acidc]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-methyl-1,3-benzothiazol-6-yl)- 1′- 2-methyl-1,3-benzothiazole-6- [1′-(trifluoromethyl)spiro[piperidine- carboxylic acid(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl]methanone(2-methyl-1,3-benzothiazol-6-yl)- 1-methylspiro[chromeno[4,3-2-methyl-1,3-benzothiazole-6- (1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] carboxylic acidc]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-methyl-1,3-benzothiazol-6-yl)- 2-methylspiro[chromeno[4,3-2-methyl-1,3-benzothiazole-6- (2-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] carboxylic acidc]pyrazole-4,4′-piperidine]-1′- yl)methanone 1,3-benzothiazol-6-yl-[1′-1′- 1,3-benzothiazole-6-carboxylic (trifluoromethyl)spiro[piperidine-(trifluoromethyl)spiro[piperidine- acid 4,4′-pyrrolo[2,1-4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1- c][1,4]benzoxazine]yl]methanone 1,3-benzothiazol-6-yl-(2- 2-methylspiro[chromeno[4,3-1,3-benzothiazole-6-carboxylic methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] acid c]pyrazole-4,4′-piperidine]-1′-yl)methanone (2-butyl-1,3-benzoxazol-5-yl)-[1′- 1′-2-butyl-1,3-benzoxazole-5- (trifluoromethyl)spiro[piperidine-(trifluoromethyl)spiro[piperidine- carboxylic acid 4,4′-pyrrolo[2,1-4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1- c][1,4]benzoxazine]yl]methanone 1-[1-(4-tert- 1-spiro[piperidine-4,4′-4-tert-butylsulfonylbenzoic acid butylsulfonylbenzoyl)spiro[piperidine-pyrrolo[2,1- 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- ylethanone yl]ethanone4-(1′-acetylspiro[piperidine-4,4′- 1-spiro[piperidine-4,4′-4-(cyclopropylsulfamoyl)benzoic pyrrolo[2,1-c][1,4]benzoxazine]-1-pyrrolo[2,1- acid carbonyl)-N-cyclopropyl- c][1,4]benzoxazine]-1′-benzenesulfonamide ylethanone 1-[1-(3-methyl-4-methylsulfonyl-1-spiro[piperidine-4,4′- 3-methyl-4-methylsulfonyl-benzoicbenzoyl)spiro[piperidine-4,4′- pyrrolo[2,1- acidpyrrolo[2,1-c][1,4]benzoxazine]-1′- c][1,4]benzoxazine]-1′- yl]ethanoneylethanone 1-[1-[4-(1-hydroxy-1-methyl- 1-spiro[piperidine-4,4′-4-(1-hydroxy-1-methyl- ethyl)benzoyl]spiro[piperidine- pyrrolo[2,1-ethyl)benzoic acid 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- ylethanone yl]ethanone1-[1-(4-isopropoxy-3-methoxy- 1-spiro[piperidine-4,4′-4-isopropoxy-3-methoxy-benzoic benzoyl)spiro[piperidine-4,4′-pyrrolo[2,1- acid pyrrolo[2,1-c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- yl]ethanone ylethanone1-[1-(4-isopropoxy-3-methyl- 1-spiro[piperidine-4,4′-4-isopropoxy-3-methyl-benzoic benzoyl)spiro[piperidine-4,4′-pyrrolo[2,1- acid pyrrolo[2,1-c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- yl]ethanone ylethanone 1-[1-[3-methoxy-4-(2-1-spiro[piperidine-4,4′- 3-methoxy-4-(2-methoxyethoxy)benzoyl]spiro[piperidine- pyrrolo[2,1-methoxyethoxy)benzoic acid 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- ylethanone yl]ethanone 1-[1-[2-1-spiro[piperidine-4,4′- 2-(difluoromethoxy)benzoic acid(difluoromethoxy)benzoyl]spiro[piperidine- pyrrolo[2,1-4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′- c][1,4]benzoxazine]-1′-ylethanone yl]ethanone

(7-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(2-fluoro-5-methoxyphenyl)methanone

Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (62 mg,0.20 mmol), 2-fluoro-5-methoxybenzoic acid (34 mg, 0.20 mmol), EDCI (38mg, 0.20 mmol), and Et₃N (56 μL, 0.40 mmol) were combined in DCM (1 mL)and the mixture was stirred for 6 h. The mixture was diluted with DCMand was washed with 1N HCl, sat. aq. sodium bicarbonate and brine. Theorganics were dried over sodium sulfate and were evaporated. The crudematerial was purified by silica gel chromatography eluting with 0-40%ethyl acetate in hexanes to provide(7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(2-fluoro-5-methoxyphenyl)methanone.ESI-MS m/z calc. 426.1. found 427.5 (M+1)⁺. Retention time: 2.12 minutes(3 min run). ¹H NMR (400 MHz, CDCl₃) δ 7.26 (d, J=8.4 Hz, 1H), 7.13-7.07(m, 2H), 7.05-6.96 (m, 2H), 6.94-6.85 (m, 2H), 6.33 (t, J=3.2 Hz, 1H),6.08-5.98 (m, 1H), 4.69 (d, J=13.1 Hz, 1H), 3.80 (s, 3H), 3.63-3.44 (m,2H), 3.33 (t, J=12.8 Hz, 1H), 2.19 (d, J=13.8 Hz, 1H), 2.09-1.96 (m,2H), 1.60 (s, 1H).

(4-(tert-Butylsulfonyl)phenyl)(1-(trifluoromethyl)spiro-[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone

1′-(Trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine](172 mg, 0.559 mmol), 4-tert-butylsulfonylbenzoic acid (176 mg, 0.727mmol), 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-aminehydrochloride (150 mg, 0.783 mmol), and triethylamine (312 μL, 2.24mmol) were combined in dichloromethane (3.4 mL). The reaction mixturewas allowed to stir for 72 hours at room temperature. The reactionmixture was washed three times with a 1M solution of hydrochloric acid,followed by three washes with a saturated aqueous solution of sodiumbicarbonate, followed by three washes of a saturated aqueous solution ofsodium chloride. The organic layer was dried over sodium sulfate,filtered, and evaporated to dryness to yield the crude product. Thecrude material was purified by reverse phase preparative chromatographyutilizing a gradient of 10-99% acetonitrile in water to yield(4-tert-butylsulfonylphenyl)-[1′-(trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone(49 mg, 16%) as a white solid. ESI-MS m/z calc. 532.2. found 533.5(M+1)⁺. Retention time: 2.10 minutes (3 min run). ¹H NMR (400 MHz, DMSO)δ 7.89 (d, J=8.0 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.0 Hz,1H), 7.35-7.25 (m, 2H), 7.25-7.16 (m, 1H), 7.03 (d, J=3.9 Hz, 1H), 6.40(d, J=3.9 Hz, 1H), 4.53-4.37 (m, 1H), 3.57-3.14 (m, 3H), 2.17-1.78 (m,4H), 1.26 (s, 9H).

The following compound was prepared using procedures reported above:

Product Name Amine or Amine•HCl Carboxylic Acid (7- 7-4-fluoro-3-methoxybenzoic chlorospiro[benzo[b]pyrrolo[1,chlorospiro[benzo[b]pyrrolo[1, acid 2-d][1,4]oxazine-4,4′-2-d][1,4]oxazine-4,4′- piperidine]-1′-yl)(4-fluoro-3- piperidine]methoxyphenyl)methanone (4-(ethylsulfonyl)phenyl)(1- 1-4-(ethylsulfonyl)benzoic acid (trifluoromethyl)spiro[benzo[b]pyrrolo[1,(trifluoromethyl)spiro[benzo][b]pyrrolo[1, 2-d][1,4]oxazine- 2-4,4′-piperidine]-1′- d][1,4]oxazine-4,4′- yl)methanone piperidine] (4-1- 4-(isopropylsulfonyl)benzoic (isopropylsulfonyl)phenyl)(1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1, acid(trifluoromethyl)spiro[benzo[b]pyrrolo[1, 2- 2-d][1,4]oxazine-d][1,4]oxazine-4,4′- 4,4′-piperidine]-1′- piperidine] yl)methanone1′-(2-(difluoromethoxy)-3- spiro[benzo[b]pyrrolo[1,2-2-(difluoromethoxy)-3- fluorobenzoyl)spiro[benzo[b]pyrrolo[1,d][1,4]oxazine-4,4′- fluorobenzoic acid 2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile piperidine]-1-carbonitrile (4-(2- 1- 4-(2-hydroxyethylsulfonyl)phenyl)(1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1, hydroxyethylsulfonyl)benzoic(trifluoromethyl)spiro[benzo[b]pyrrolo[1, 2- acid 2-d][1,4]oxazine-d][1,4]oxazine-4,4′- 4,4′-piperidine]-1′- piperidine] yl)methanone(3-methyl-4- 1- 3-methyl-4- (methylsulfonyl)phenyl)(1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1, (methylsulfonyl)benzoic acid(trifluoromethyl)spiro[benzo[b]pyrrolo[1, 2- 2-d][1,4]oxazine-d][1,4]oxazine-4,4′- 4,4′-piperidine]-1′- piperidine] yl)methanone(3-(hydroxymethyl)-4- 1- 3-(hydroxymethyl)-4- isopropoxyphenyl)(1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1, isopropoxybenzoic acid(trifluoromethyl)spiro[benzo[b]pyrrolo[1, 2- 2-d][1,4]oxazine-d][1,4]oxazine-4,4′- 4,4′-piperidine]-1′- piperidine] yl)methanone1-[3-(hydroxymethyl)-2- spiro[piperidine-4,4′-3-(hydroxymethyl)-2-methoxy- methoxy- pyrrolo[2,1- benzoic acidbenzoyl]spiro[piperidine-4,4′- c][1,4]benzoxazine]-1′- pyrrolo[2,1-carbonitrile c][1,4]benzoxazine]-1′- carbonitrile 1-(2-ethoxy-3-fluoro-spiro[piperidine-4,4′- 2-ethoxy-3-fluoro-benzoic acidbenzoyl)spiro[piperidine-4,4′- pyrrolo[2,1- pyrrolo[2,1-c][1,4]benzoxazine]-1′- c][1,4]benzoxazine]-1′- carbonitrilecarbonitrile 1-(2-fluoro-3-isopropoxy- spiro[piperidine-4,4′-2-fluoro-3-isopropoxy-benzoic benzoyl)spiro[piperidine-4,4′-pyrrolo[2,1- acid pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- carbonitrile carbonitrile 1-[4-spiro[piperidine-4,4′- 4-(trifluoromethyl)benzoic acid(trifluoromethyl)benzoyl]spiro[piperidine- pyrrolo[2,1-4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′- c][1,4]benzoxazine]-1′-carbonitrile carbonitrile 7′-fluoro-1-[4-methoxy-3-7′-fluorospiro[piperidine- 4-methoxy-3-(trifluoromethyl)benzoyl]spiro[piperidine- 4,4′-pyrrolo[2,1-(trifluoromethyl)benzoic acid 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- carbonitrile carbonitrile1-(4-isopropylsulfonyl-3- spiro[piperidine-4,4′-4-isopropylsulfonyl-3-methyl- methyl- pyrrolo[2,1- benzoic acidbenzoyl)spiro[piperidine-4,4′- c][1,4]benzoxazine]-1′- pyrrolo[2,1-carbonitrile c][1,4]benzoxazine]-1′- carbonitrile1-(4-isopropylsulfonyl-2- spiro[piperidine-4,4′-4-isopropylsulfonyl-2-methyl- methyl- pyrrolo[2,1- benzoic acidbenzoyl)spiro[piperidine-4,4′- c][1,4]benzoxazine]-1′- pyrrolo[2,1-carbonitrile c][1,4]benzoxazine]-1′- carbonitrile 1-[4-(1-spiro[piperidine-4,4′- 4-(1-methylsulfonylethyl)benzoyl]spiro[piperidine- pyrrolo[2,1-methylsulfonylethyl)benzoic 4,4′- c][1,4]benzoxazine]-1′- acidpyrrolo[2,1- carbonitrile c][1,4]benzoxazine]-1′- carbonitrile1-[4-(1-hydroxy-1-methyl- spiro[piperidine-4,4′- 4-(1-hydroxy-1-methyl-ethyl)benzoyl]spiro[piperidine- pyrrolo[2,1- ethyl)benzoic acid4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′- c][1,4]benzoxazine]-1′-carbonitrile carbonitrile 1-[4- spiro[piperidine-4,4′-4-(difluoromethoxy)benzoic (difluoromethoxy)benzoyl]spiro[piperidine-pyrrolo[2,1- acid 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- carbonitrile carbonitrile 1-(3-chloro-4-fluoro-spiro[piperidine-4,4′- 3-chloro-4-fluoro-benzoic acidbenzoyl)spiro[piperidine-4,4′- pyrrolo[2,1- pyrrolo[2,1-c][1,4]benzoxazine]-1′- c][1,4]benzoxazine]-1′- carbonitrilecarbonitrile 1-(2-chloro-4-fluoro- spiro[piperidine-4,4′-2-chloro-4-fluoro-benzoic acid benzoyl)spiro[piperidine-4,4′-pyrrolo[2,1- pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- carbonitrile carbonitrile (1-cyano-1′-(4- (1-4-isopropylsulfonylbenzoic(isopropylsulfonyl)benzoyl)spiro[benzo[b]pyrrolo[1,cyanospiro[benzo[b]pyrrolo[1, acid 2- 2-d][1,4]oxazine-4,4′-d][1,4]oxazine-4,4′- piperidine]-7-yl)methyl piperidine]-7-yl)methylacetate acetate 4-(1′-cyanospiro[piperidine- spiro[piperidine-4,4′-4-(isopropylsulfamoyl)benzoic 4,4′-pyrrolo[2,1- pyrrolo[2,1- acidc][1,4]benzoxazine]-1- c][1,4]benzoxazine]-1′- carbonyl)-N-isopropyl-carbonitrile benzenesulfonamide 1-[4-(1-hydroxy-2-methyl-spiro[piperidine-4,4′- 4-(1-hydroxy-2-methyl-propyl)benzoyl]spiro[piperidine- pyrrolo[2,1- propyl)benzoic acid4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′- c][1,4]benzoxazine]-1′-carbonitrile carbonitrile 1-[4-methylsulfinyl-3- spiro[piperidine-4,4′-4-methylsulfinyl-3- (trifluoromethyl)benzoyl]spiro[piperidine-pyrrolo[2,1- (trifluoromethyl)benzoic acid 4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′- c][1,4]benzoxazine]-1′- carbonitrilecarbonitrile 1-[4-(2-hydroxy-2-methyl- spiro[piperidine-4,4′-4-(2-hydroxy-2-methyl- propyl)benzoyl]spiro[piperidine- pyrrolo[2,1-propyl)benzoic acid 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- carbonitrile carbonitrile 1-(4- 7′-4-isopropylsulfonylbenzoic isopropylsulfonylbenzoyl)-7′-(methoxymethyl)spiro[piperidine- acid (methoxymethyl)spiro[piperidine-4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- carbonitrile carbonitrile 1-[4-methylsulfonyl-3-spiro[piperidine-4,4′- 4-methylsulfonyl-3-(trifluoromethyl)benzoyl]spiro[piperidine- pyrrolo[2,1-(trifluoromethyl)benzoic acid 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- carbonitrile carbonitrile1-(6-tert-butylpyridine-3- spiro[piperidine-4,4′-6-tert-butylpyridine-3- carbonyl)spiro[piperidine-4,4′- pyrrolo[2,1-carboxylic acid pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- carbonitrile carbonitrile1-[4-(2-hydroxy-1,1-dimethyl- spiro[piperidine-4,4′-4-(2-hydroxy-1,1-dimethyl- ethyl)benzoyl]spiro[piperidine- pyrrolo[2,1-ethyl)benzoic acid 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- carbonitrile carbonitrile1-[3-(hydroxymethyl)-2- spiro[piperidine-4,4′-3-(hydroxymethyl)-2-methyl- methyl- pyrrolo[2,1- benzoic acidbenzoyl]spiro[piperidine-4,4′- c][1,4]benzoxazine]-1′- pyrrolo[2,1-carbonitrile c][1,4]benzoxazine]-1′- carbonitrile1-[4-(1-hydroxy-1-methyl- spiro[piperidine-4,4′-4-(1-hydroxy-1-methyl-ethyl)- ethyl)-2-methoxy- pyrrolo[2,1-2-methoxy-benzoic acid benzoyl]spiro[piperidine-4,4′-c][1,4]benzoxazine]-1′- pyrrolo[2,1- carbonitrilec][1,4]benzoxazine]-1′- carbonitrile 1-[4-(2- spiro[piperidine-4,4′-4-(2-hydroxyethoxy)benzoic hydroxyethoxy)benzoyl]spiro[piperidine-pyrrolo[2,1- acid 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- carbonitrile carbonitrile1-[4-[(1R)-1,2-dihydroxy-1- spiro[piperidine-4,4′-4-[(1R)-1,2-dihydroxy-1- methyl- pyrrolo[2,1- methyl-ethyl]benzoic acidethyl]benzoyl]spiro[piperidine- c][1,4]benzoxazine]-1′-4,4′-pyrrolo[2,1- carbonitrile c][1,4]benzoxazine]-1′- carbonitrile1-[4-[(1S)-1,2-dihydroxy-1- spiro[piperidine-4,4′-4-[(1S)-1,2-dihydroxy-1- methyl- pyrrolo[2,1- methyl-ethyl]benzoic acidethyl]benzoyl]spiro[piperidine- c][1,4]benzoxazine]-1′-4,4′-pyrrolo[2,1- carbonitrile c][1,4]benzoxazine]-1′- carbonitrile1-[4-(1-hydroxy-1-methyl- spiro[piperidine-4,4′-4-(1-hydroxy-1-methyl-ethyl)- ethyl)-2-methyl- pyrrolo[2,1-2-methyl-benzoic acid benzoyl]spiro[piperidine-4,4′-c][1,4]benzoxazine]-1′- pyrrolo[2,1- carbonitrilec][1,4]benzoxazine]-1′- carbonitrile 1-[4-(3-hydroxyoxetan-3-spiro[piperidine-4,4′- 4-(3-hydroxyoxetan-3-yl)benzoyl]spiro[piperidine- pyrrolo[2,1- yl)benzoic acid4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′- c][1,4]benzoxazine]-1′-carbonitrile carbonitrile 4-(1′-cyanospiro[piperidine-spiro[piperidine-4,4′- 4-(2- 4,4′-pyrrolo[2,1- pyrrolo[2,1-hydroxyethylsulfamoyl)benzoic c][1,4]benzoxazine]-1-c][1,4]benzoxazine]-1′- acid carbonyl)-N-(2- carbonitrilehydroxyethyl)benzenesulfonamide 4-(1′-cyanospiro[piperidine-spiro[piperidine-4,4′- 4-[(2-hydroxy-1-methyl- 4,4′-pyrrolo[2,1-pyrrolo[2,1- ethyl)sulfamoyl]benzoic acid c][1,4]benzoxazine]-1-c][1,4]benzoxazine]-1′- carbonyl)-N-(2-hydroxy-1- carbonitrile methyl-ethyl)benzenesulfonamide N-tert-butyl-4-(1′- spiro[piperidine-4,4′-4-(tert-butylsulfamoyl)benzoic cyanospiro[piperidine-4,4′- pyrrolo[2,1-acid pyrrolo[2,1- c][1,4]benzoxazine]-1′- c][1,4]benzoxazine]-1-carbonitrile carbonyl)benzenesulfonamide methyl 2-(1′-spiro[piperidine-4,4′- 3-methoxy-2-methoxycarbonyl-cyanospiro[piperidine-4,4′- pyrrolo[2,1- benzoic acid pyrrolo[2,1-c][1,4]benzoxazine]-1′- c][1,4]benzoxazine]-1- carbonitrilecarbonyl)-6-methoxy-benzoate 1-[4-[(1S)-1,2-dihydroxy-1-spiro[piperidine-4,4′- 4-[(1S)-1,2-dihydroxy-1- methyl-ethyl]-3-methyl-pyrrolo[2,1- methyl-ethyl]-3-methyl-benzoicbenzoyl]spiro[piperidine-4,4′- c][1,4]benzoxazine]-1′- acid pyrrolo[2,1-carbonitrile c][1,4]benzoxazine]-1′- carbonitrile1-[4-[(1R)-1,2-dihydroxy-1- spiro[piperidine-4,4′-4-[(1R)-1,2-dihydroxy-1- methyl-ethyl]-3-methyl- pyrrolo[2,1-methyl-ethyl]-3-methyl-benzoic benzoyl]spiro[piperidine-4,4′-c][1,4]benzoxazine]-1′- acid pyrrolo[2,1- carbonitrilec][1,4]benzoxazine]-1′- carbonitrile 1-[4-[(2S)-2,3-spiro[piperidine-4,4′- 4-[(2S)-2,3- dihydroxypropoxy]-3- pyrrolo[2,1-dihydroxypropoxy]-3-methoxy- methoxy- c][1,4]benzoxazine]-1′- benzoicacid benzoyl]spiro[piperidine-4,4′- carbonitrile pyrrolo[2,1-c][1,4]benzoxazine]-1′- carbonitrile 1-[4-[(2R)-2,3-spiro[piperidine-4,4′- 4-[(2R)-2,3- dihydroxypropoxy]-3- pyrrolo[2,1-dihydroxypropoxy]-3-methoxy- methoxy- c][1,4]benzoxazine]-1′- benzoicacid benzoyl]spiro[piperidine-4,4′- carbonitrile pyrrolo[2,1-c][1,4]benzoxazine]-1′- carbonitrile 1-[2-(hydroxymethyl)-4-spiro[piperidine-4,4′- 2-(hydroxymethyl)-4- isopropoxy- pyrrolo[2,1-isopropoxy-benzoic acid benzoyl]spiro[piperidine-4,4′-c][1,4]benzoxazine]-1′- pyrrolo[2,1- carbonitrilec][1,4]benzoxazine]-1′- carbonitrile 1-(4- spiro[piperidine-4,4′-4-hydroxybenzoic acid hydroxybenzoyl)spiro[piperidine- pyrrolo[2,1-4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′- c][1,4]benzoxazine]-1′-carbonitrile carbonitrile 1-(4-hydroxy-3-methyl- spiro[piperidine-4,4′-4-hydroxy-3-methyl-benzoic benzoyl)spiro[piperidine-4,4′- pyrrolo[2,1-acid pyrrolo[2,1- c][1,4]benzoxazine]-1′- c][1,4]benzoxazine]-1′-carbonitrile carbonitrile 2-[4-(1′-cyanospiro[piperidine-spiro[piperidine-4,4′- 4-(carboxymethyloxy)-3- 4,4′-pyrrolo[2,1-pyrrolo[2,1- methyl-benzoic acid c][1,4]benzoxazine]-1-c][1,4]benzoxazine]-1′- carbonyl)-2-methyl- carbonitrile phenoxy]aceticacid 2-[4-(1′-cyanospiro[piperidine- spiro[piperidine-4,4′-4-(2-hydroxy-1,1-dimethyl-2- 4,4′-pyrrolo[2,1- pyrrolo[2,1-oxo-ethoxy)benzoic acid c][1,4]benzoxazine]-1- c][1,4]benzoxazine]-1′-carbonyl)phenoxy]-2-methyl- carbonitrile propanoic acid1-(4-hydroxy-3-methoxy- spiro[piperidine-4,4′-4-hydroxy-3-methoxy-benzoic benzoyl)spiro[piperidine-4,4′- pyrrolo[2,1-acid pyrrolo[2,1- c][1,4]benzoxazine]-1′- c][1,4]benzoxazine]-1′-carbonitrile carbonitrile 1-[4-(1-amino-1-methyl- spiro[piperidine-4,4′-4-(1-amino-1-methyl- ethyl)benzoyl]spiro[piperidine- pyrrolo[2,1-ethyl)benzoic acid 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- carbonitrile carbonitrile 1-[4-(azetidin-3-spiro[piperidine-4,4′- 4-(azetidin-3-yloxy)benzoicyloxy)benzoyl]spiro[piperidine- pyrrolo[2,1- acid 4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′- c][1,4]benzoxazine]-1′- carbonitrilecarbonitrile 1-(2-methyl-4-methylsulfonyl- spiro[piperidine-4,4′-2-methyl-4-methylsulfonyl- benzoyl)spiro[piperidine-4,4′- pyrrolo[2,1-benzoic acid pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- carbonitrile carbonitrile 1-[4-[(2R)-2,3-spiro[piperidine-4,4′- 4-[(2R)-2,3-dihydroxypropoxy]benzoyl]spiro[piperidine- pyrrolo[2,1-dihydroxypropoxy]benzoic acid 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- carbonitrile carbonitrile 1-[4-[(2S)-2,3-spiro[piperidine-4,4′- 4-[(2S)-2,3-dihydroxypropoxy]benzoyl]spiro[piperidine- pyrrolo[2,1-dihydroxypropoxy]benzoic acid 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1′-c][1,4]benzoxazine]-1′- carbonitrile carbonitrile4-(1′-cyanospiro[piperidine- spiro[piperidine-4,4′- 4-(3-4,4′-pyrrolo[2,1- pyrrolo[2,1- hydroxypropylsulfamoyl)benzoicc][1,4]benzoxazine]-1- c][1,4]benzoxazine]-1′- acid carbonyl)-N-(3-carbonitrile hydroxypropyl)benzenesulfonamide2-[4-(1′-cyanospiro[piperidine- spiro[piperidine-4,4′-4-(2-hydroxy-1,1-dimethyl-2- 4,4′-pyrrolo[2,1- pyrrolo[2,1-oxo-ethoxy)-3-methyl-benzoic c][1,4]benzoxazine]-1-c][1,4]benzoxazine]-1′- acid carbonyl)-2-methyl-phenoxy]- carbonitrile2-methyl-propanoic acid 1-[3-(hydroxymethyl)-4-(1-spiro[piperidine-4,4′- 3-(hydroxymethyl)-4-(1- hydroxy-1-methyl-pyrrolo[2,1- hydroxy-1-methyl- ethyl)benzoyl]spiro[piperidine-c][1,4]benzoxazine]-1′- ethyl)benzoic acid 4,4′-pyrrolo[2,1-carbonitrile c][1,4]benzoxazine]-1′- carbonitrile [4-methoxy-3- 1′-4-methoxy-3- (trifluoromethyl)phenyl]-(1′-methylsulfonylspiro[piperidine- (trifluoromethyl)benzoic acidmethylsulfonylspiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl)methanone[4-(1-hydroxy-1-methyl- 1′- 4-(1-hydroxy-1-methyl- ethyl)phenyl]-(1′-methylsulfonylspiro[piperidine- ethyl)benzoic acidmethylsulfonylspiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl)methanone[3-(hydroxymethyl)-4- 1′- 3-(hydroxymethyl)-4- isopropoxy-phenyl]-(1′-methylsulfinylspiro[piperidine- isopropoxy-benzoic acidmethylsulfinylspiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl)methanone(4-tert-butoxy-3-methoxy- 1′- 4-tert-butoxy-3-methoxy- phenyl)-(1′-methylsulfinylspiro[piperidine- benzoic acidmethylsulfinylspiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl)methanone(4-tert-butylsulfonylphenyl)- 1′- 4-tert-butylsulfonylbenzoic (1′-methylsulfonylspiro[piperidine- acid methylsulfonylspiro[piperidine-4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]c][1,4]benzoxazine]-1- yl)methanone [3-(hydroxymethyl)-4- 1′-3-(hydroxymethyl)-4- isopropoxy-phenyl]-(1′-methylsulfonylspiro[piperidine- isopropoxy-benzoic acidmethylsulfonylspiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl)methanone2-[2-methoxy-4-[1′- 1′- 4-(2-amino-2-oxo-ethoxy)-3-(trifluoromethyl)spiro[piperidine- (trifluoromethyl)spiro[piperidine-methoxy-benzoic acid 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1- c][1,4]benzoxazine] carbonyl]phenoxy]acetamide[4-(1-hydroxy-1-methyl- 1′- 4-(1-hydroxy-1-methyl- ethyl)phenyl]-[1′-(trifluoromethyl)spiro[piperidine- ethyl)benzoic acid(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl]methanone (4- 1′-4-cyclopropylsulfonylbenzoic cyclopropylsulfonylphenyl)-(trifluoromethyl)spiro[piperidine- acid [1′- 4,4′-pyrrolo[2,1-(trifluoromethyl)spiro[piperidine- c][1,4]benzoxazine] 4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1- yl]methanone [4-(2-hydroxy-2-methyl- 1′-4-(2-hydroxy-2-methyl- propyl)phenyl]-[1′-(trifluoromethyl)spiro[piperidine- propyl)benzoic acid(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl]methanone[4-(1-hydroxy-2-methyl- 1′- 4-(1-hydroxy-2-methyl- propyl)phenyl]-[1′-(trifluoromethyl)spiro[piperidine- propyl)benzoic acid(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl]methanone(4-tetrahydrofuran-3- 1′- 4-tetrahydrofuran-3- ylsulfonylphenyl)-[1′-(trifluoromethyl)spiro[piperidine- ylsulfonylbenzoic acid(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl]methanone[4-(3-hydroxyoxetan-3- 1′- 4-(3-hydroxyoxetan-3- yl)phenyl]-[1′-(trifluoromethyl)spiro[piperidine- yl)benzoic acid(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl]methanone[4-(2-hydroxyethoxy)phenyl]- 1′- 4-(2-hydroxyethoxy)benzoic [1′-(trifluoromethyl)spiro[piperidine- acid(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl]methanone[3-(hydroxymethyl)-2- 1′- 3-(hydroxymethyl)-2-methoxy-methoxy-phenyl]-[1′- (trifluoromethyl)spiro[piperidine- benzoic acid(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl]methanone[6-(1-hydroxy-1-methyl- 1′- 6-(1-hydroxy-1-methyl-ethyl)-3-pyridyl]-[1′- (trifluoromethyl)spiro[piperidine-ethyl)pyridine-3-carboxylic (trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1- acid 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]c][1,4]benzoxazine]-1- yl]methanone [4- 1′- 4-[cyclopropyl(hydroxy)methyl]phenyl]- (trifluoromethyl)spiro[piperidine-[cyclopropyl(hydroxy)methyl]benzoic [1′- 4,4′-pyrrolo[2,1- acid(trifluoromethyl)spiro[piperidine- c][1,4]benzoxazine] 4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1- yl]methanone [3-(hydroxymethyl)-4-(1- 1′-3-(hydroxymethyl)-4-(1- hydroxy-1-methyl-(trifluoromethyl)spiro[piperidine- hydroxy-1-methyl- ethyl)phenyl]-[1′-4,4′-pyrrolo[2,1- ethyl)benzoic acid (trifluoromethyl)spiro[piperidine-c][1,4]benzoxazine] 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1-yl]methanone [4-[(1S)-1,2-dihydroxy-1- 1′- 4-[(1S)-1,2-dihydroxy-1-methyl-ethyl]phenyl]-[1′- (trifluoromethyl)spiro[piperidine-methyl-ethyl]benzoic acid (trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]c][1,4]benzoxazine]-1- yl]methanone [4-[(1R)-1,2-dihydroxy-1- 1′-4-[(1R)-1,2-dihydroxy-1- methyl-ethyl]phenyl]-[1′-(trifluoromethyl)spiro[piperidine- methyl-ethyl]benzoic acid(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl]methanone[4-[(3S)-tetrahydrofuran-3- 1′- 4-[(3S)-tetrahydrofuran-3-yl]sulfonylphenyl]-[1′- (trifluoromethyl)spiro[piperidine-yl]sulfonylbenzoic acid (trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]c][1,4]benzoxazine]-1- yl]methanone [4-[(3R)-tetrahydrofuran-3- 1′-4-[(3R)-tetrahydrofuran-3- yl]sulfonylphenyl]-[1′-(trifluoromethyl)spiro[piperidine- yl]sulfonylbenzoic acid(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl]methanoneN,2-dimethyl-4-[1′- 1′- 3-methyl-4- (trifluoromethyl)spiro[piperidine-(trifluoromethyl)spiro[piperidine- (methylsulfamoyl)benzoic acid4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1-c][1,4]benzoxazine] carbonyl]benzenesulfonamide 2-methyl-2-[4-[1′- 1′-4-(2-hydroxy-1,1-dimethyl-2- (trifluoromethyl)spiro[piperidine-(trifluoromethyl)spiro[piperidine- oxo-ethyl)sulfonylbenzoic acid4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1-c][1,4]benzoxazine] carbonyl]phenyl]sulfonyl- propanoic acid[4-(2-hydroxy-1,1-dimethyl- 1′- 4-(2-hydroxy-1,1-dimethyl-ethyl)sulfonylphenyl]-[1′- (trifluoromethyl)spiro[piperidine-ethyl)sulfonylbenzoic acid (trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]c][1,4]benzoxazine]-1- yl]methanone N,N,2-trimethyl-4-[1′- 1′-4-(dimethylsulfamoyl)-3- (trifluoromethyl)spiro[piperidine-(trifluoromethyl)spiro[piperidine- methyl-benzoic acid 4,4′-pyrrolo[2,1-4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1- c][1,4]benzoxazine]carbonyl]benzenesulfonamide (5-isopropoxy-6-methyl-2- 1′-5-isopropoxy-6-methyl- pyridyl)-[1′- (trifluoromethyl)spiro[piperidine-pyridine-2-carboxylic acid (trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]c][1,4]benzoxazine]-1- yl]methanone (4-hydroxy-3-methyl-phenyl)- 1′-4-hydroxy-3-methyl-benzoic [1′- (trifluoromethyl)spiro[piperidine- acid(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl]methanone[2-(difluoromethoxy)phenyl]- 1′- 2-(difluoromethoxy)benzoic [1′-(trifluoromethyl)spiro[piperidine- acid(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl]methanone[3-fluoro-4-(1-hydroxy-1- 1′- 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]-[1′- (trifluoromethyl)spiro[piperidine-methyl-ethyl)benzoic acid (trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]c][1,4]benzoxazine]-1- yl]methanone (5-methoxy-2-pyridyl)-[1′- 1′-5-methoxypyridine-2- (trifluoromethyl)spiro[piperidine-(trifluoromethyl)spiro[piperidine- carboxylic acid 4,4′-pyrrolo[2,1-4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1- c][1,4]benzoxazine]yl]methanone (5-methyl-2-pyridyl)-[1′- 1′- 5-methylpyridine-2-carboxylic(trifluoromethyl)spiro[piperidine- (trifluoromethyl)spiro[piperidine-acid 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1-c][1,4]benzoxazine] yl]methanone (5-ethyl-2-pyridyl)-[1′- 1′-5-ethylpyridine-2-carboxylic (trifluoromethyl)spiro[piperidine-(trifluoromethyl)spiro[piperidine- acid 4,4′-pyrrolo[2,1-4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1- c][1,4]benzoxazine]yl]methanone (5-isopropoxy-2-pyridyl)-[1′- 1′- 5-isopropoxypyridine-2-(trifluoromethyl)spiro[piperidine- (trifluoromethyl)spiro[piperidine-carboxylic acid 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1- c][1,4]benzoxazine] yl]methanone(2-ethoxy-3-pyridyl)-[1′- 1′- 2-ethoxypyridine-3-carboxylic(trifluoromethyl)spiro[piperidine- (trifluoromethyl)spiro[piperidine-acid 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1- c][1,4]benzoxazine]-1-c][1,4]benzoxazine] yl]methanone (2-pyrrolidin-1-yl-3-pyridyl)- 1′-2-pyrrolidin-1-ylpyridine-3- [1′- (trifluoromethyl)spiro[piperidine-carboxylic acid (trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1-4,4′-pyrrolo[2,1- c][1,4]benzoxazine] c][1,4]benzoxazine]-1-yl]methanone [2-(4-fluorophenoxy)-3- 1′- 2-(4-fluorophenoxy)pyridine-3-pyridyl]-[1′- (trifluoromethyl)spiro[piperidine- carboxylic acid(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl]methanone(2-phenoxy-3-pyridyl)-[1′- 1′- 2-phenoxypyridine-3-(trifluoromethyl)spiro[piperidine- (trifluoromethyl)spiro[piperidine-carboxylic acid 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1- c][1,4]benzoxazine] yl]methanone(3-tert-butylsulfonyl-2- 1′- 3-tert-butylsulfonylthiophene-thienyl)-[1′- (trifluoromethyl)spiro[piperidine- 2-carboxylic acid(trifluoromethyl)spiro[piperidine- 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine] c][1,4]benzoxazine]-1- yl]methanone4H-furo[3,2-b]pyrrol-5-yl-[1′- 1′- 4H-furo[3,2-b]pyrrole-5-(trifluoromethyl)spiro[piperidine- (trifluoromethyl)spiro[piperidine-carboxylic acid 4,4′-pyrrolo[2,1- 4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1- c][1,4]benzoxazine] yl]methanone[3-(hydroxymethyl)-2- 1- 3-(hydroxymethyl)-2-methoxy-methoxy-phenyl]-(1- methylspiro[chromeno[4,3- benzoic acidmethylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone N-cyclopropyl-4-(1- 1- 4-methylspiro[chromeno[4,3- methylspiro[chromeno[4,3-(cyclopropylsulfamoyl)benzoic c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] acid carbonyl)benzenesulfonamide[4-(1-hydroxy-2-methyl- 1- 4-(1-hydroxy-2-methyl- propyl)phenyl]-(1-methylspiro[chromeno[4,3- propyl)benzoic acid methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone[4-(1-hydroxy-1-methyl- 1- 4-(1-hydroxy-1-methyl- ethyl)phenyl]-(1-methylspiro[chromeno[4,3- ethyl)benzoic acid methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone[4-(2-hydroxy-2-methyl- 1- 4-(2-hydroxy-2-methyl- propyl)phenyl]-(1-methylspiro[chromeno[4,3- propyl)benzoic acid methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone[2-(difluoromethoxy)phenyl]- 1- 2-(difluoromethoxy)benzoic [1-(trifluoromethyl)spiro[chromeno[4, acid(trifluoromethyl)spiro[chromeno[4, 3-c]pyrazole-4,4′- 3-c]pyrazole-4,4′-piperidine] piperidine]-1′-yl]methanone 2-[2-methoxy-4-(1- ammonia; 1-4-(2-amino-2-oxo-ethoxy)-3- methylspiro[chromeno[4,3-methylspiro[chromeno[4,3- methoxy-benzoic acidc]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine]carbonyl)phenoxy]acetamide [4-(2-hydroxyethoxy)phenyl]- 1-4-(2-hydroxyethoxy)benzoic (1-methylspiro[chromeno[4,3-methylspiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)methanone [4-(1-hydroxy-1-methyl- 1-4-(1-hydroxy-1-methyl-ethyl)- ethyl)-2-methoxy-phenyl]-(1-methylspiro[chromeno[4,3- 2-methoxy-benzoic acidmethylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone[3-(hydroxymethyl)-2-methyl- 1- 3-(hydroxymethyl)-2-methyl- phenyl]-(1-methylspiro[chromeno[4,3- benzoic acid methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone[4-(3-hydroxyoxetan-3- 1- 4-(3-hydroxyoxetan-3- yl)phenyl]-(1-methylspiro[chromeno[4,3- yl)benzoic acid methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone[4-(1-hydroxy-1-methyl- 1- 4-(1-hydroxy-1-methyl-ethyl)-ethyl)-2-methyl-phenyl]-(1- methylspiro[chromeno[4,3- 2-methyl-benzoicacid methylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone (5-isopropoxy-6-methyl-2-1- 5-isopropoxy-6-methyl- pyridyl)-(1- methylspiro[chromeno[4,3-pyridine-2-carboxylic acid methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone[2-(difluoromethoxy)phenyl]- 2- 2-(difluoromethoxy)benzoic [2-(trifluoromethyl)spiro[chromeno[4, acid(trifluoromethyl)spiro[chromeno[4, 3-c]pyrazole-4,4′- 3-c]pyrazole-4,4′-piperidine] piperidine]-1′-yl]methanone (4-isopropoxy-3-methoxy- 2-4-isopropoxy-3-methoxy- phenyl)-(2- methylspiro[chromeno[4,3- benzoicacid methylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-tert-butylsulfonylphenyl)- 2- 4-tert-butylsulfonylbenzoic [2-(trifluoromethyl)spiro[chromeno[4, acid(trifluoromethyl)spiro[chromeno[4, 3-c]pyrazole-4,4′- 3-c]pyrazole-4,4′-piperidine] piperidine]-1′-yl]methanone [2-(difluoromethoxy)phenyl]- 2-2-(difluoromethoxy)benzoic (2-methylspiro[chromeno[4,3-methylspiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)methanone N-isopropyl-4-(2- 2-4-(isopropylsulfamoyl)benzoic methylspiro[chromeno[4,3-methylspiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] carbonyl)benzenesulfonamide[4-(1-hydroxy-2-methyl- 2- 4-(1-hydroxy-2-methyl- propyl)phenyl]-(2-methylspiro[chromeno[4,3- propyl)benzoic acid methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone[4-(1-hydroxy-1-methyl- 2- 4-(1-hydroxy-1-methyl- ethyl)phenyl]-(2-methylspiro[chromeno[4,3- ethyl)benzoic acid methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone[3-(hydroxymethyl)-4- 2- 3-(hydroxymethyl)-4- isopropoxy-phenyl]-(2-methylspiro[chromeno[4,3- isopropoxy-benzoic acidmethylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-isopropoxy-3-methyl- 2-4-isopropoxy-3-methyl-benzoic phenyl)-(2- methylspiro[chromeno[4,3- acidmethylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone (2-fluoro-4-isopropoxy- 2-2-fluoro-4-isopropoxy-benzoic phenyl)-(2- methylspiro[chromeno[4,3- acidmethylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone [4-(2-hydroxy-2-methyl- 2-4-(2-hydroxy-2-methyl- propyl)phenyl]-(2- methylspiro[chromeno[4,3-propyl)benzoic acid methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanoneN-cyclopropyl-4-(2- 2- 4- methylspiro[chromeno[4,3-methylspiro[chromeno[4,3- (cyclopropylsulfamoyl)benzoicc]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine] acidcarbonyl)benzenesulfonamide N-tert-butyl-4-(2- 2-4-(tert-butylsulfamoyl)benzoic methylspiro[chromeno[4,3-methylspiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] carbonyl)benzenesulfonamide(8-fluoro-2-methyl- 8-fluoro-2-methyl- 2-(trifluoromethoxy)benzoicspiro[chromeno[4,3- spiro[chromeno[4,3- acidc]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine] yl)-[2-(trifluoromethoxy)phenyl]methanone 4-(8-fluoro-2-methyl-8-fluoro-2-methyl- 4-(isopropylsulfamoyl)benzoic spiro[chromeno[4,3-spiro[chromeno[4,3- acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] carbonyl)-N-isopropyl- benzenesulfonamide(8-fluoro-2-methyl- 8-fluoro-2-methyl- 4-isopropoxy-3-methoxy-spiro[chromeno[4,3- spiro[chromeno[4,3- benzoic acidc]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine]yl)-(4-isopropoxy-3-methoxy- phenyl)methanone (8-fluoro-2-methyl-8-fluoro-2-methyl- 3-(hydroxymethyl)-4- spiro[chromeno[4,3-spiro[chromeno[4,3- isopropoxy-benzoic acidc]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine]yl)-[3-(hydroxymethyl)-4- isopropoxy-phenyl]methanone(8-fluoro-2-methyl- 8-fluoro-2-methyl- 4-(1-hydroxy-1-methyl-spiro[chromeno[4,3- spiro[chromeno[4,3- ethyl)benzoic acidc]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine]yl)-[4-(1-hydroxy-1-methyl- ethyl)phenyl]methanone (8-fluoro-2-methyl-8-fluoro-2-methyl- 4-(1-hydroxy-1-methyl-ethyl)- spiro[chromeno[4,3-spiro[chromeno[4,3- 2-methyl-benzoic acidc]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine]yl)-[4-(1-hydroxy-1-methyl- ethyl)-2-methyl- phenyl]methanone(8-fluoro-2-methyl- 8-fluoro-2-methyl- 4-isopropoxybenzoic acidspiro[chromeno[4,3- spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] yl)-(4- isopropoxyphenyl)methanone[3-(hydroxymethyl)-4-(1- 2- 3-(hydroxymethyl)-4-(1- hydroxy-1-methyl-methylspiro[chromeno[4,3- hydroxy-1-methyl- ethyl)phenyl]-(2-c]pyrazole-4,4′-piperidine] ethyl)benzoic acid methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone N,2-dimethyl-4-(2- 2-3-methyl-4- methylspiro[chromeno[4,3- methylspiro[chromeno[4,3-(methylsulfamoyl)benzoic acid c]pyrazole-4,4′-piperidine]-1′-c]pyrazole-4,4′-piperidine] carbonyl)benzenesulfonamide(4-tert-butoxy-3-methoxy- 2- 4-tert-butoxy-3-methoxy- phenyl)-(2-methylspiro[chromeno[4,3- benzoic acid methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(4-isopropoxy-2-methyl- 2- 4-isopropoxy-2-methyl-benzoic phenyl)-(2-methylspiro[chromeno[4,3- acid methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(2-methylspiro[chromeno[4,3- 2- quinoline-8-carboxylic acidc]pyrazole-4,4′-piperidine]-1′- methylspiro[chromeno[4,3-yl)-(8-quinolyl)methanone c]pyrazole-4,4′-piperidine](6-isopropoxy-3-pyridyl)-(2- 2- 6-isopropoxypyridine-3-methylspiro[chromeno[4,3- methylspiro[chromeno[4,3- carboxylic acidc]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine] yl)methanone(2-methylspiro[chromeno[4,3- 2- quinoline-4-carboxylic acidc]pyrazole-4,4′-piperidine]-1′- methylspiro[chromeno[4,3-yl)-(4-quinolyl)methanone c]pyrazole-4,4′-piperidine][2-(difluoromethoxy)-3-fluoro- 2- 2-(difluoromethoxy)-3-fluoro-phenyl]-(2- methylspiro[chromeno[4,3- benzoic acidmethylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone(3-ethoxy-4-methoxy-phenyl)- 2- 3-ethoxy-4-methoxy-benzoic(2-methylspiro[chromeno[4,3- methylspiro[chromeno[4,3- acidc]pyrazole-4,4′-piperidine]-1′- c]pyrazole-4,4′-piperidine] yl)methanone(5-isopropoxy-6-methyl-2- 2- 5-isopropoxy-6-methyl- pyridyl)-(2-methylspiro[chromeno[4,3- pyridine-2-carboxylic acidmethylspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone

(1-Methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)(m-tolyl)methanone

3-Methylbenzoyl chloride (14 mg, 0.09 mmol) was added to a mixture of1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride(30 mg, 0.09 mmol), triethylamine (64 μL, 0.46 mmol), and DMF (0.7 mL)at 25° C. The mixture was allowed to stir at 50° C. overnight before itwas cooled to 25° C. The mixture was filtered and then purified byreverse phase-HPLC to give(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)(m-tolyl)methanone.ESI-MS m/z calc. 373.2. found 374.2 (M+1)⁺. Retention time: 2.04 minutes(4 min run).

The following compound was prepared using procedures reported above:

Product Name Amine or Amine•HCl Acid Chloride (7-chloro-1-methyl-1H-7-chloro-1-methyl-1H- 2-(trifluoromethoxy)- spiro[chromeno[4,3-spiro[chromeno[4,3- benzoyl chloride c]pyrazole-4,4′- c]pyrazole-4,4′-piperidine]-1′-yl)(2- piperidine] (trifluoromethoxy)- phenyl)methanone(8-chloro-1-methyl-1H- 8-chloro-1-methyl-1H- 2-(trifluoromethoxy)-spiro[chromeno[4,3- spiro[chromeno[4,3- benzoyl chloridec]pyrazole-4,4′- c]pyrazole-4,4′- piperidine]-1′-yl)(2- piperidine](trifluoromethoxy)- phenyl)methanone

(3-Fluoro-4-hydroxy-phenyl)-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone

A mixture of 1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]bishydrochloric acid (507 mg, 1.7 mmol), 3-fluoro-4-hydroxy-benzoic acid(271 mg, 1.7 mmol), triethylamine (727 μL, 5.2 mmol), and EDCI (333 mg,1.7 mmol) in dichloromethane (10 mL) were stirred at room temperaturefor 16 hours. The reaction was diluted with dichloromethane and washedwith 1N HCl, saturated sodium bicarbonate solution, and brine. Theorganics were dried over sodium sulfate and evaporated. Thecrude-material was purified by column chromatography eluting with 0-10%methanol in dichloromethane to yield(3-fluoro-4-hydroxy-phenyl)-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(330 mg, 48%). ESI-MS m/z calc 393.4. found 394.3 (M+1)⁺. Retentiontime: 1.39 minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 10.41 (s, 1H),7.73 (d, J=7.7 Hz, 1H), 7.46 (s, 1H), 7.32-7.23 (m, 2H), 7.15-7.04 (m,3H), 6.98 (t, J=8.5 Hz, 1H), 4.10 (s, 3H), 3.52-3.19 (m, 4H), 1.99-1.85(m, 4H).

The following compounds were prepared using the procedure reportedabove:

Product Name Amine or Amine•HCl Carboxylic Acid2-isopropoxy-5-(1-methyl-1H- 1-methylspiro[chromeno[4,3-3-cyano-4-isopropoxy-benzoic spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride acidc]pyrazole-4,4′-piperidine]-1′- ylcarbonyl)benzonitrile 5-(1-methyl-1H-1-methylspiro[chromeno[4,3- 3-cyano-4-[2- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride(trifluoromethoxy)ethoxy]benzoic c]pyrazole-4,4′-piperidine]-1′- acidylcarbonyl)-2-(2- (trifluoromethoxy)ethoxy)benzonitrile [3-methyl-4-[2-1-methylspiro[chromeno[4,3- 3-methyl-4-[2-(trifluoromethoxy)ethoxy]phenyl]-c]pyrazole-4,4′-piperidine]dihydrochloride(trifluoromethoxy)ethoxy]benzoic (1-methyl-1H- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone [3-methoxy-4-[2-1-methylspiro[chromeno[4,3- 3-methoxy-4-[2-(trifluoromethoxy)ethoxy]phenyl]-c]pyrazole-4,4′-piperidine]dihydrochloride(trifluoromethoxy)ethoxy]benzoic (1-methyl-1H- acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methylindazol-7-yl)-(1-1-methylspiro[chromeno[4,3- 1-methylindazole-7-carboxylic methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methylindazol-4-yl)-(1-1-methylspiro[chromeno[4,3- 1-methylindazole-4-carboxylic methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-methyl-1H-1-methylspiro[chromeno[4,3- quinoxaline-5-carboxylic acidspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridec]pyrazole-4,4′-piperidine]-1′- yl)quinoxalin-5-yl-methanone(4-hydroxy-3-methoxy- 1-methylspiro[chromeno[4,3-4-hydroxy-3-methoxy-benzoic phenyl)-(1-methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (3-methoxy-4-tert-butoxy-1-methylspiro[chromeno[4,3- 3-methoxy-4-tert-butoxy-phenyl)-(1-methyl-1H- c]pyrazole-4,4′-piperidine]dihydrochloride benzoicacid spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′- yl)methanone(2,4-diethoxy-3-methyl- 1-methylspiro[chromeno[4,3-2,4-diethoxy-3-methyl-benzoic phenyl)-(1-methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-(difluoromethoxy)-3-1-methylspiro[chromeno[4,3- 4-(difluoromethoxy)-3-methoxyphenyl)(1-methyl-1H- c]pyrazole-4,4′-piperidine]dihydrochloridemethoxybenzoic acid spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-yl)methanone 1-isopropyl-4-(1-methyl-1H- 1-methylspiro[chromeno[4,3-1-isopropyl-2-oxo-1,2- spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride dihydropyridine-4-carboxylicc]pyrazole-4,4′-piperidine]-1′- acid ylcarbonyl)pyridin-2(1H)-one(4-fluoro-3-methylphenyl)(1- 1-methylspiro[chromeno[4,3-4-fluoro-3-methylbenzoic acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (1-ethyl-1H- 1-ethyl-1H-4-(isopropylsulfonyl)benzoic spiro[chromeno[4,3-spiro[chromeno[4,3-c]pyrazole- acid c]pyrazole-4,4′-piperidine]-1′-4,4′-piperidine] yl)(4- (isopropylsulfonyl)phenyl)methanoneN-isopropyl-N-methyl-4-(1- 1-methylspiro[chromeno[4,3- 4-(N-isopropyl-N-methyl-1H- c]pyrazole-4,4′-piperidine]dihydrochloridemethylsulfamoyl)benzoic acid spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- ylcarbonyl)benzenesulfonamide (4-1-methylspiro[chromeno[4,3- 4-(isopropylsulfinyl)benzoic(isopropylsulfinyl)phenyl)(1- c]pyrazole-4,4′-piperidine]dihydrochlorideacid methyl-1H- spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-yl)methanone (8-chloro-1-methyl-1H- 8-chloro-1-methyl-1H-2-(difluoromethoxy)benzoic spiro[chromeno[4,3-spiro[chromeno[4,3-c]pyrazole- acid c]pyrazole-4,4′-piperidine]-1′-4,4′-piperidine] yl)(2- (difluoromethoxy)phenyl)methanone(7-chloro-1-methyl-1H- 7-chloro-1-methyl-1H- 2-(difluoromethoxy)benzoicspiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole- acidc]pyrazole-4,4′-piperidine]-1′- 4,4′-piperidine] yl)(2-(difluoromethoxy)phenyl)methanone (4-tert-butoxyphenyl)(1-1-methylspiro[chromeno[4,3- 4-tert-butoxybenzoic acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (2,4-1-methylspiro[chromeno[4,3- 2,4- bis(difluoromethoxy)phenyl)(1-c]pyrazole-4,4′-piperidine]dihydrochloride bis(difluoromethoxy)benzoicmethyl-1H- acid spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-yl)methanone (4-(ethylsulfonyl)phenyl)(1- 1-methylspiro[chromeno[4,3-4-(ethylsulfonyl)benzoic acid methyl-1H-c]pyrazole-4,4′-piperidine]dihydrochloride spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′- yl)methanone (4-(tert-1-methylspiro[chromeno[4,3- 4-(tert-butylsulfonyl)benzoicbutylsulfonyl)phenyl)(1- c]pyrazole-4,4′-piperidine]dihydrochloride acidmethyl-1H- spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′-yl)methanone (1-methyl-1H- 1-methylspiro[chromeno[4,3- 2-(2,2,2-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloridetrifluoroethoxy)benzoic acid c]pyrazole-4,4′-piperidine]-1′-yl)(2-(2,2,2- trifluoroethoxy)phenyl)methanone (1-ethyl-1H- 1-ethyl-1H-3-fluoro-2-methoxybenzoic spiro[chromeno[4,3-spiro[chromeno[4,3-c]pyrazole- acid c]pyrazole-4,4′-piperidine]-1′-4,4′-piperidine] yl)(3-fluoro-2- methoxyphenyl)methanone (2- 1-ethyl-1H-2-(difluoromethoxy)benzoic (difluoromethoxy)phenyl)(1-spiro[chromeno[4,3-c]pyrazole- acid ethyl-1H-spiro[chromeno[4,3-4,4′-piperidine] c]pyrazole-4,4′-piperidine]-1′- yl)methanone(1-ethyl-1H- 1-ethyl-1H- 2-(trifluoromethoxy)benzoic spiro[chromeno[4,3-spiro[chromeno[4,3-c]pyrazole- acid c]pyrazole-4,4′-piperidine]-1′-4,4′-piperidine] yl)(2- (trifluoromethoxy)phenyl)methanone(2-(difluoromethoxy)-3- 1-ethyl-1H- 2-(difluoromethoxy)-3-fluorophenyl)(1-ethyl-1H- spiro[chromeno[4,3-c]pyrazole- fluorobenzoicacid spiro[chromeno[4,3- 4,4′-piperidine]c]pyrazole-4,4′-piperidine]-1′- yl)methanone methyl 2-(1-ethyl-1H-1-methylspiro[chromeno[4,3- 2-(methoxycarbonyl)benzoicspiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloride acidc]pyrazole-4,4′-piperidine]-1′- ylcarbonyl)benzoate(7-fluoro-1-methyl-1H- 7-fluoro-1-methyl-1H- 2-(trifluoromethoxy)benzoicspiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole- acidc]pyrazole-4,4′-piperidine]-1′- 4,4′-piperidine] yl)(2-(trifluoromethoxy)phenyl)methanone (2- 7-fluoro-1-methyl-1H-2-(difluoromethoxy)benzoic (difluoromethoxy)phenyl)(7-spiro[chromeno[4,3-c]pyrazole- acid fluoro-1-methyl-1H- 4,4′-piperidine]spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]-1′- yl)methanone(7-fluoro-1-methyl-1H- 7-fluoro-1-methyl-1H-4-(isopropylsulfonyl)benzoic spiro[chromeno[4,3-spiro[chromeno[4,3-c]pyrazole- acid c]pyrazole-4,4′-piperidine]-1′-4,4′-piperidine] yl)(4- (isopropylsulfonyl)phenyl)methanone(7-fluoro-1-methyl-1H- 7-fluoro-1-methyl-1H- 4-isopropoxy-3-spiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole- methoxybenzoic acidc]pyrazole-4,4′-piperidine]-1′- 4,4′-piperidine] yl)(4-isopropoxy-3-methoxyphenyl)methanone (7-fluoro-1-methyl-1H- 7-fluoro-1-methyl-1H-2-methoxybenzoic acid spiro[chromeno[4,3- spiro[chromeno[4,3-c]pyrazole-c]pyrazole-4,4′-piperidine]-1′- 4,4′-piperidine] yl)(2-methoxyphenyl)methanone methyl 4-(7-fluoro-1-methyl-1-methylspiro[chromeno[4,3- 4-(methoxycarbonyl)benzoic1H-spiro[chromeno[4,3- c]pyrazole-4,4′-piperidine]dihydrochloride acidc]pyrazole-4,4′-piperidine]-1′- ylcarbonyl)benzoate

(4-Propoxy-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanoneStep 1:(4-Fluoro-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone

Spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (100 mg, 0.361mmol), 4-fluoro-3-(trifluoromethyl)benzoic acid (75.2 mg, 0.361 mmol),and triethylamine (110 mg, 151 μL, 1.08 mmol) were combined in DMF (3mL) and HATU (137 mg, 0.361 mmol) was added. The reaction was stirred atroom temperature for 1 h and was concentrated. The residue was purifiedby column chromatography (silica gel: 0-50% ethyl acetate in hexanes) togive(4-fluoro-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone(113 mg, 73%). ESI-MS m/z calc. 430.1. found 431.1 (M+1)⁺; Retentiontime: 2.24 minutes (4 min run).

Step 2:(4-Propoxy-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone

(4-Fluoro-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone(22 mg, 0.051 mmol), nPrOH (12 μL, 0.15 mmol), and NaH (60%, 6.1 mg,0.15 mmol) were combined in acetonitrile (1 mL) and the reaction mixturewas heated at 70° C. for 1 h. The reaction mixture was filtered andpurified by reverse phase HPLC to provide(4-propoxy-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone.ESI-MS m/z calc. 470.2. found 471.2 (M−1)⁻; Retention time: 2.83 minutes(4 min run).

The following compounds were synthesized using the procedures describedabove:(R)-spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl(4-(tetrahydrofuran-3-yloxy)-3-(trifluoromethyl)phenyl)methanone,(S)-spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl(4-(tetrahydrofuran-3-yloxy)-3-(trifluoromethyl)phenyl)methanone,spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl(4-((tetrahydrofuran-2-yl)methoxy)-3-(trifluoromethyl)phenyl)methanone,(4-(2-(dimethylamino)ethoxy)-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone,and(S)-(4-(2-methoxypropoxy)-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone.

2-(2-Methoxy-4-(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)phenoxy)aceticacid Step 1:(4-Hydroxy-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone

4-Hydroxy-3-methoxy-benzoic acid (304 mg, 1.81 mmol) was stirred withthionyl chloride (645 mg, 395 μL, 5.42 mmol) in dichloromethane and 2drops of DMF were added. After stirring for 2.5 h, the excess thionylchloride and dichloromethane were removed in vacuo. The residue wasadded to a mixture ofspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (500 mg, 1.81mmol), 1,4-dioxane (6.5 mL), and triethylamine (760 μL, 5.42 mmol). Themixture was stirred for 18 h at 90° C. before it was cooled to roomtemperature and was evaporated to dryness. The residue was dissolved inethyl acetate, filtered and washed with 1N HCl (2×), a saturated sodiumbicarbonate solution (2×), and brine. The organic layer was dried oversodium sulfate and was evaporated to dryness. The residue was purifiedby column chromatography (0-100% EtOAc/hexane) to give(4-hydroxy-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone(394 mg, 56%). ESI-MS m/z calc. 390.2. found 391.2 (M+1)⁺; Retentiontime: 2.56 minutes (4 min run).

Step 2: Methyl2-(2-methoxy-4-(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)phenoxy)acetate

To(4-hydroxy-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone(200 mg, 0.512 mmol), sodium iodide (38.4 mg, 0.256 mmol), Cs₂CO₃ (334mg, 1.03 mmol), and DCE (5.0 mL) was added methyl 2-bromoacetate (49 μL,0.51 mmol). The mixture was stirred at 60° C. for 18 h. Additionalmethyl 2-bromoacetate (1.0 mmol) was added and the mixture was heatedfor 3 h at 60° C. The mixture was cooled and then filtered. The solventwas evaporated under reduced pressure and the crude product was purifiedby column chromatography on silica gel (0-30% ethyl acetate/DCM) toyield methyl2-(2-methoxy-4-(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)phenoxy)acetate(140 mg, 59%). ESI-MS m/z calc. 462.2. found 463.5 (M+1)⁺; Retentiontime: 2.68 minutes (4 min run).

Step 3:2-(2-Methoxy-4-(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)phenoxy)aceticacid

To a solution of methyl2-(2-methoxy-4-(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)phenoxy)acetate(140 mg, 0.303 mmol) in THF (4 mL) was added LiOH (600 μL of 2.0 M, 1.2mmol) and the mixture was stirred at room temperature for 19 h. Themixture was filtered and was purified by HPLC using 5 mM HCl/water andMeOH to yield2-(2-methoxy-4-(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)phenoxy)aceticacid. ESI-MS m/z calc. 448.2. found 449.3 (M+1)⁺; Retention time: 5.90minutes (15 min run).

(3-Methoxy-4-(2-methoxypropan-2-yl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanoneStep 1: (4-(2-Hydroxypropan-2-yl)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone

4-(1-Hydroxy-1-methyl-ethyl)-3-methoxy-benzoic acid (120 mg, 0.573mmol), spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (167 mg,0.573 mmol), triethylamine (320 μL, 2.29 mmol), and EDC (110 mg, 0.573mmol) were combined in DCM (5.8 mL). The reaction mixture was allowed tostir at room temperature for 16 h. The reaction mixture was washed threetimes with a 1M solution of hydrochloric acid, followed by three washeswith a saturated aqueous solution of sodium bicarbonate, followed bythree washes of a saturated aqueous solution of sodium chloride. Theorganic layer was dried over sodium sulfate, filtered, and evaporated todryness to provide(4-(2-hydroxypropan-2-yl)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone.ESI-MS m/z calc. 432.0. found 433.1 (M+1)⁺; Retention time: 1.61 minutes(3 min run).

Step 2: (3-Methoxy-4-(2-methoxypropan-2-yl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone

(4-(2-Hydroxypropan-2-yl)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone(crude material from step 1) was dissolved in a mixture of THF (3 mL)and DMF (3 mL). NaH (28 mg, 0.69 mmol) was added and the reactionmixture was allowed to stir for 2 minutes. MeI (54 μL, 0.86 mmol) wasthen added and the reaction mixture was allowed to stir for 1 h. Thereaction mixture was evaporated to dryness and the residue was suspendedin 25 mL of dichloromethane. The suspension was washed two times with a1M solution of hydrochloric acid, followed by two washes with asaturated aqueous solution of sodium bicarbonate, followed by two washesof a saturated aqueous solution of sodium chloride. The organic layerwas dried over sodium sulfate, filtered, and evaporated to dryness toyield the crude product. The crude material was purified by columnchromatography utilizing a gradient of 0-35% ethyl acetate in hexanesgive(3-methoxy-4-(2-methoxypropan-2-yl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone(94 mg, 35% over 2 steps). ESI-MS m/z calc. 446.2. found 447.5 (M+1)⁺;Retention time: 7.60 minutes (15 min run). ¹H NMR (400 MHz, DMSO) δ7.68-7.65 (m, 1H), 7.50-7.49 (m, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.17-6.98(m, 5H), 6.29-6.28 (m, 1H), 6.18-6.17 (m, 1H), 4.49-4.34 (m, 1H), 3.83(s, 3H), 3.80-3.41 (m, 3H), 3.13 (s, 3H), 2.11-1.81 (m, 41-1) and 1.50(s, 6H).

(7-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-methoxy-4-(3-methoxyoxetan-3-yl)phenyl)methanonewas also prepared using the procedures described above.

(4-Methoxy-3-(methylsulfonyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanoneStep 1:(4-Fluoro-3-(methylsulfonyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone

Spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (257 mg, 0.928mmol), 4-fluoro-3-methylsulfonyl-benzoic acid (203 mg, 0.928 mmol),triethylamine (518 μL, 3.71 mmol), and EDC (196 mg, 1.02 mmol) werecombined in dichloromethane (10 mL) and the reaction mixture was stirredat room temperature for 4 d. The reaction mixture was washed three timeswith a 1M solution of hydrochloric acid, followed by three washes with asaturated aqueous solution of sodium bicarbonate, followed by threewashes of a saturated aqueous solution of sodium chloride. The organiclayer was dried over sodium sulfate, filtered, and evaporated to drynessto yield the crude product. The crude material was purified columnchromatography utilizing a gradient of 0-75% ethyl acetate in hexanes toyield(4-fluoro-3-methylsulfonyl-phenyl)-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl-methanone(222 mg, 54%) as a colorless oil. ESI-MS m/z calc. 440.1. found 441.1(M+1)⁺; Retention time: 1.51 minutes (3 min run).

Step 2:(4-Methoxy-3-(methylsulfonyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone

(4-Fluoro-3-methylsulfonyl-phenyl)-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl-methanone(44 mg, 0.10 mmol) and MeOH (12 μL, 0.30 mmol) were combined in DMF (1mL). NaH (60%, 12 mg, 0.30 mmol) was added and the reaction mixture wasstirred for 10 minutes. The mixture was filtered and was purified byreverse phase preparative liquid chromatography utilizing a gradient of10-99% acetonitrile in water containing 5 mM hydrochloric acid to give(4-methoxy-3-(methylsulfonyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone.ESI-MS m/z calc. 452.1. found 453.5 (M+1)⁺; Retention time: 1.78 minutes(3 min run). ¹H NMR (400 MHz, DMSO) δ 7.87 (d, J=2.0 Hz, 1H), 7.86-7.81(m, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.50 (s, 1H), 7.36 (d, J=8.6 Hz, 1H),7.22-7.02 (m, 3H), 6.28 (t, J=3.1 Hz, 1H), 6.16 (d, J=2.3 Hz, 1H),4.52-4.18 (m, 1H), 4.00 (s, 3H), 3.58 (s, 3H), 3.28 (s, 3H), 1.98 (s,4H).

The following compounds were synthesized using the procedures describedabove:(3-(methylsulfonyl)-4-propoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone,(4-isopropoxy-3-(methylsulfonyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone,(4-(isopentyloxy)-3-(methylsulfonyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone,and(4-(2-methoxyethoxy)-3-(methylsulfonyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone.

(5-(Hydroxymethyl)-2,4-dimethoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone

2,4-Dimethoxy-5-(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)benzaldehyde(65 mg, 0.15 mmol) was suspended in MeOH (1 mL). NaBH₄ (60 mg, 1.6 mmol)was added and the reaction mixture was allowed to stir for 15 minutes.The reaction mixture was filtered and was then purified by reverse phasepreparative liquid chromatography utilizing a gradient of 20-99%methanol in water containing no modifier to give(5-(hydroxymethyl)-2,4-dimethoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yOmethanone.ESI-MS m/z calc. 434.2. found 435.5 (M+1)⁺; Retention time: 1.63 minutes(3 min run).

(7-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-cyclopropyl-3-methoxyphenyl)methanone

To a microwave vial was added Pd-FibreCat (42 mg, 0.0065 mmol),(4-bromo-3-methoxyphenyl)(7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone(63 mg, 0.13 mmol), cyclopropylboronic acid (17 mg, 0.19 mmol), DMF (0.7mL), and K₂CO₃ (190 μL of 2.0 M, 0.39 mmol). The reaction vessel waspurged with nitrogen and the mixture was heated at 120° C. overnight.The mixture was filtered and was purified by prep-HPLC (20-99% MeOH:H₂Owith HCl modifier) to give(7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-cyclopropyl-3-methoxyphenyl)methanone.ESI-MS m/z calc. 448.2. found 449.4 (M+1)⁺; Retention time: 3.32 minutes(4 min run).

(S)-(8-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(2,3-dihydroxypropoxy)-3-methoxyphenyl)methanone

(R)-(8-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3-methoxyphenyl)methanone(41 mg, 0.076 mmol) and 4-methylbenzenesulfonic acid hydrate (2.9 mg,0.015 mmol) were dissolved in MeOH (760 μL) and H₂O (76 μL) was added.The reaction mixture was heated at 80° C. for 45 min. The mixture wasfiltered and the residue was purified by reverse phase HPLC using 5 mMHCl/H₂O and MeOH to yield(S)-(8-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(2,3-dihydroxypropoxy)-3-methoxyphenyl)methanone.ESI-MS ni/z calc. 498.2. found 499.3 (M+1)⁺; Retention time: 4.72minutes (15 min run).

The following compounds were synthesized using the procedures describedabove:(S)-(4-(2,3-dihydroxypropoxy)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanoneand(R)-(4-(2,3-dihydroxypropoxy)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone.

(4-Ethyl-3-methoxyphenyl)(7-(hydroxymethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanoneStep 1: Methyl1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylate

A solution of 4-ethyl-3-methoxy-benzoic acid (450 mg, 2.5 mmol), HATU(940 mg, 2.5 mmol), methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-carboxylate(830 mg, 2.5 mmol), and Et₃N (1.7 mL, 9.9 mmol) in DMF (8 mL) wasstirred at room temperature overnight. The reaction was diluted withethyl acetate and washed with saturated sodium bicarbonate solution. Theorganics were dried over sodium sulfate, filtered and evaporated toyield a crude mixture that was purified by silica gel chromatographyeluting with 0-30% EtOAc in hexanes to yield methyl1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylate(1.1 g, quant). ESI-MS m/z calc. 460.5. found 461.5 (M+1)⁺; Retentiontime: 2.08 minutes (3 min run).

Step 2:1′-(4-Ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylicacid

A solution of methyl1-(4-ethyl-3-methoxy-benzoyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-carboxylate(1.1 g, 2.5 mmol) in LiOH (2.5 mL of 4.0 M, 9.9 mmol) and dioxane (5 mL)was stirred at 50° C. for 1 hour. The reaction was diluted with ethylacetate and washed with water. The aqueous was acidified with 1N HCl andthe product was extracted into ethyl acetate. The organics were driedover sodium sulfate, filtered and evaporated to yield a crude productthat was used in the next step without further purification (0.60 g,53%). ESI-MS m/z calc. 446.5. found 447.5 (M+1)⁺; Retention time: 1.84minutes (3 min run).

Step 3:(4-Ethyl-3-methoxyphenyl)(7-(hydroxymethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone

To1-(4-ethyl-3-methoxy-benzoyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-carboxylicacid (550 mg, 1.2 mmol) in tetrahydrofuran (2.2 mL) at 0° C. was addedtriethylamine (200 μL, 1.4 mmol) then isobutyl chloroformate (180 μL,1.4 mmol). The mixture was stirred for 30 min then filtered. Thefiltrate was added dropwise to a solution of sodium borohydride (70 mg,1.8 mmol) in water (770 μL) at 0° C. The mixture was allowed to slowlyreach room temperature before it was concentrated to ⅓ volume, dilutedwith ethyl acetate and washed with 1M HCl. The organics were dried oversodium sulfate, filtered and evaporated to yield(4-ethyl-3-methoxyphenyl)(7-(hydroxymethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone(330 mg, 62%). ESI-MS m/z calc. 432.5. found 433.5 (M+1)⁺; Retentiontime: 1.78 minutes (3 min run).

(4-Ethyl-3-methoxyphenyl)(7-(methoxymethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone

MeI (7.2 μL, 0.12 mmol) was added to a solution of(4-ethyl-3-methoxy-phenyl)-[7′-(hydroxymethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone(50 mg, 0.12 mmol) and NaH (4.6 mg, 0.12 mmol) in DMF (1 mL) and wasstirred at room temperature for 1 hour. The reaction was filtered andpurified by reverse phase LC-MS (10-99% CH₃CN/H₂O). Pure fractions werecombined and evaporated to yield(4-ethyl-3-methoxyphenyl)(7-(methoxymethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone.ESI-MS m/z calc. 446.5. found 447.5 (M+1)⁺; Retention time: 2.11 minutes(3 min run).

(7-((Dimethylamino)methyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-ethyl-3-methoxyphenyl)methanoneStep 1:1′-(4-Ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carbaldehyde

A solution of(4-ethyl-3-methoxy-phenyl)-[7′-(hydroxymethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone(270 mg, 0.62 mmol) and manganese dioxide (270 mg, 3.1 mmol) indichloromethane (5 mL) was stirred at 60° C. overnight. The reaction wasfiltered, evaporated and submitted to the next step without furtherpurificaton. ESI-MS m/z calc. 430.5. found 431.7 (M+1)⁺; Retention time:2.01 minutes (3 min run).

Step 2:(7-((Dimethylamino)methyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-ethyl-3-methoxyphenyl)methanone

A solution of1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carbaldehyde(88 mg, 0.20 mmol) N,N-dimethylamine hydrochloride (83 mg, 1.0 mmol),Et₃N (140 mL, 1.0 mmol) and NaHB(OAc)₃ (130 mg, 0.60 mmol) in DMF (1 mL)was stirred at room temperature overnight. The reaction mixture wasfiltered and purified by reverse phase LC-MS (10-99% CH₃CN/H₂O) to yield(7-((dimethylamino)methyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-ethyl-3-methoxyphenyl)methanone.ESI-MS m/z calc. 459.6. found 460.5 (M+1)⁺; Retention time: 1.40 minutes(3 min run).

1′-(4-Ethyl-3-methoxybenzoyl)-N,N-dimethylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxamide

A solution of1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylicacid (40 mg, 0.09 mmol), HATU (34 mg, 0.090 mmol), N,N-dimethylaminehydrochloride (7.3 mg, 0.090 mmol) and iPr₂NEt (62 pit, 0.36 mmol) inDMF (1 mL) was stirred at room temperature overnight. The reactionmixture was filtered and purified by reverse phase LC-MS (10-99%CH₃CN/H₂O). Pure fractions were combined and evaporated to yield1′-(4-ethyl-3-methoxybenzoyl)-N,N-dimethylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxamide.ESI-MS m/z calc. 473.6. found 474.5 (M+1)⁺; Retention time: 1.80 minutes(3 min run).

1′-(4-Ethyl-3-methoxybenzoyl)-N-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxamide

A solution of1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylicacid (40 mg, 0.090 mmol), HATU (34 mg, 0.090 mmol), N-methylaminehydrochloride (6.0 mg, 0.090 mmol) and iPr₂NEt (62 μL, 0.36 mmol) in DMF(1 mL) was stirred at room temperature overnight. The reaction mixturewas filtered and purified by reverse phase LC-MS (10-99% CH₃CN/H₂O).Pure fractions were combined and evaporated to yield1′-(4-ethyl-3-methoxybenzoyl)-N-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxamide.ESI-MS m/z calc. 459.5. found 460.5 (M+1)⁺; Retention time: 1.73 minutes(3 min run).

(7-(Aminomethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-ethyl-3-methoxyphenyl)methanone

NaBH₄ (17.7 mg, 0.47 mmol) was slowly added to a solution of1-(4-ethyl-3-methoxy-benzoyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-carbonitrile(20 mg, 0.050 mmol) and dichlorocobalt hexahydrate (22 mg, 0.090 mmol)in MeOH (1 mL) and was stirred at room temperature for 10 minutes. Thereaction mixture was filtered and purified by reverse phase LC-MS(10-99% CH₃CN/H₂O) to yield(7-(aminomethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-ethyl-3-methoxyphenyl)methanone.ESI-MS m/z calc. 431.5. found 432.5 (M+1)⁺; Retention time: 1.44 minutes(3 min run).

(4-Isopropoxy-3-methylphenyl)(1-(methylsulfonyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanoneStep 1:(4-Isopropoxy-3-methylphenyl)(1-(methylthio)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone

A solution of 1-chloropyrrolidine-2,5-dione (92 mg, 0.70 mmol) in drydichloromethane (3.2 mL) was added dropwise at −10° C. to a solution ofmethylsulfanylmethane (82 μL, 1.1 mmol) in dry dichloromethane (800 μL)over a period of 5 minutes. The reaction was allowed to warm to roomtemperature and was stirred for 30 minutes. The mixture was then cooledto −55° C. and a solution of(4-isopropoxy-3-methyl-phenyl)-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl-methanone(210 mg, 0.49 mmol) in dry dichloromethane (800 μL) was added dropwise.The cooling bath was removed and the mixture was gradually warmed up toroom temperature and was stirred overnight. The solvent was removedunder vacuum and the pink residue that was obtained was dissolved in drytoluene (7 mL) and was heated at 50° C. for 5 minutes. The solvent wasremoved to afford(4-isopropoxy-3-methylphenyl)(1-(methylthio)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone(250 mg, 78%). ESI-MS m/z calc. 462.2. found 463.5 (M+1)⁺; Retentiontime: 2.43 minutes (3 min run).

Step 2:(4-Isopropoxy-3-methylphenyl)(1-(methylsulfonyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone

To a solution of(4-isopropoxy-3-methylphenyl)(1-(methylthio)spiro[benzo[b]-pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone(250 mg, 0.54 mmol) in dry dichloromethane (2 mL) at 0° C. was added3-chlorobenzenecarboperoxoic acid (93 mg, 0.54 mmol). After stirring 10minutes at 0° C. the cooling bath was removed. The reaction was dilutedwith dichloromethane (25 mL) and saturated sodium bicarbonate (10 mL).The organic layer was separated and the aqueous layer was extractedtwice with dichloromethane (2×25 mL). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentrated.The residue was purified by column chromatography (silica gel: 5-40%EtOAc in hexanes) then reverse phase HPLC 10-99% acetonitrile in water(HCl modifier) to give(4-isopropoxy-3-methylphenyl)(1-(methylsulfonyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone.¹H NMR (400 MHz, CDCl₃) δ 8.60 (d, J=7.9 Hz, 1H), 7.31-7.21 (m, 4H),7.21-7.13 (m, 2H), 6.84 (d, J=8.7 Hz, 1H), 6.17 (d, J=4.0 Hz, 1H),4.65-4.52 (m, 1H), 4.25 (bs, 2H), 3.55-3.36 (m, 2H), 3.10 (s, 3H), 2.22(s, 3H), 2.18-1.87 (m, 4H) and 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc.494.6. found 495.5 (M+1)⁺; Retention time: 1.98 minutes (3 min run).

1′-(4-Ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrileStep 1:(Z)-1′-(4-Ethyl-3-methoxybenzoyl)spiro[benzo[b]-pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehydeoxime

A solution of1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde(950 mg, 2.21 mmol) in ethanol (4.7 mL) was heated at 60° C. A solutionof hydroxylamine hydrochloride (693 mg, 9.97 mmol) and sodium acetate(1.38 g, 16.8 mmol) in water (4.7 mL) was added to the carbaldehydesolution. The reaction mixture was heated at 70° C. for 30 minutesbefore it was cooled to room temperature. Water was added and theproduct formed a white precipitate which was collected by filtration.The solids were washed with water and toluene, and dried under reducedpressure to give(Z)-1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehydeoxime (847 mg).

Step 2:1′-(4-Ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile

Acetic anhydride (4.0 mL, 42 mmol) was added to(Z)-1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehydeoxime (847 mg from previous step). The reaction mixture was heated at140° C. for 3.5 h then cooled to room temperature and poured onto ice.Dichloromethane (30 mL) was added followed by sodium bicarbonate (0.7g). The organic phase was then separated and the aqueous layer wasextracted twice with dichloromethane. The combined organic layers werewashed with brine, dried, filtered, and concentrated to give a yellowoil. The crude material was purified by column chromatography (silicagel: 5-45% EtOAc in hexanes) to give1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile(944 mg, 69%). ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J=8.0 Hz, 1H),7.22-7.16 (m, 1H), 7.15-7.08 (m, J=7.6 Hz, 3H), 7.00 (d, J=4.0 Hz, 1H),6.93-6.87 (m, 2H), 6.08 (d, J=4.0 Hz, 1H), 4.64 (s, 1H), 3.83 (s, 3H),3.65-3.14 (m, 3H), 2.62 (q, J=7.5 Hz, 2H), 2.27-1.67 (m, 4H), 1.16 (t,J=7.5 Hz, 3H). ESI-MS m/z calc. 427.5. found 428.5 (M+1)⁺; Retentiontime: 2.08 minutes (3 min run).

(1-(Aminomethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-isopropoxy-3-methylphenyl)methanone

To a solution of1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile(255 mg, 0.572 mmol) in MeOH (15.3 mL) at 0° C. was added dichlorocobalt(149 mg, 1.14 mmol) followed by portion wise addition of NaBH₄ (216. mg,5.72 mmol). The reaction mixture was allowed to stir for 15 minutes atroom temperature before it was cooled to 0° C. and acidified with 1MHCl. The solvent was removed under reduced pressure, and the residue waspartitioned between EtOAc (50 mL) and aqueous saturated NaHCO₃ (15 mL).The aqueous phase was extracted with EtOAc (2×50 mL). The combinedorganic phases were dried with Na₂SO₄, filtered and concentrated to give(1-(aminomethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-isopropoxy-3-methylphenyl)methanone(170 mg, 67%). ESI-MS m/z calc. 445.6. found 446.5 (M+1)⁺; Retentiontime: 1.45 minutes (3 min run).

N-((1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]pyrrolo-[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methyl)formamide

A solution of(1-(aminomethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-isopropoxy-3-methylphenyl)methanonehydrochloride (60 mg, 0.13 mmol) in ethyl formate (109 μL, 1.35 mmol)was heated at 50° C. overnight. The solvent was removed under reducedpressure and the product was purified by reverse phase HPLC 10-99%acetonitrile in water (HCl modifier) to giveN-((1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]pyrrolo-[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methyl)formamide.¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.40 (d, J=7.8 Hz, 1H),7.30-7.22 (m, 1H), 7.20-7.01 (m, 3H), 6.83 (d, J=8.1 Hz, 1H), 6.28 (d,J=3.5 Hz, 1H), 5.99 (d, J=3.6 Hz, 1H), 5.89 (s, 1H), 4.77 (d, J=5.0 Hz,2H), 4.62-4.52 (m, 1H), 3.50 (s, 2H), 2.21 (s, 3H), 2.17-1.78 (m, 4H),1.70 (s, 2H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 473.6. found474.5 (M+1)⁺; Retention time: 1.80 minutes (3 min run).

N-((1′-(4-isopropoxy-3-methylbenzoyll)spiro[benzo[b]-pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yOmethyl)acetamide

Crude(1-(aminomethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-isopropoxy-3-methylphenyl)methanone(49 mg, 0.11 mmol) was dissolved in a solution of dry dichloromethane(0.5 mL) and pyridine (0.3 mL) and was cooled to 0° C. Acetic anhydride(52 μL, 0.55 mmol) was added and the reaction mixture was stirred for 30minutes. The reaction mixture was quenched by the addition of methanol(0.5 mL), concentrated, and purified by reverse phase HPLC [10-99%acetonitrile in water (HCl modifier)] to giveN-((1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methyl)acetamide.¹H NMR (400 MHz, CDCl₃) δ 7.41 (d, J=7.9 Hz, 1H), 7.33-7.21 (m, 2H),7.13 (d, J=4.2 Hz, 2H), 7.10-7.02 (m, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.26(d, J=3.4 Hz, 1H), 5.99 (d, J=3.5 Hz, 1H), 5.68 (s, 1H), 4.71 (d, J=4.7Hz, 2H), 4.64-4.50 (m, 1H), 3.50 (s, 2H), 2.22 (s, 3H), 2.17-1.76 (m,7H), 1.67 (s, 2H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 487.6. found488.5 (M+1)⁺; Retention time: 1.81 minutes (3 min run).

(7-Chloro-1-(hydroxymethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-methoxy-4-(trifluoromethyl)phenyl)methanone Step 1:7-Chloro-1′-(3-methoxy-4-(trifluoromethyl)benzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde

POCl₃ (150 μL, 1.5 mmol) was added dropwise at 0° C. under N₂ to dry DMF(120 μL, 1.5 mmol). The reaction mixture was left for 20 min at thistemperature, which led to the formation of a white solid. A solution of(7′-chlorospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl)-[4-methoxy-3-(trifluoromethyl)phenyl]methanone(490 mg, 1.0 mmol) in dry DMF (3.7 mL) was added dropwise and thecooling bath was removed and stirring was continued for an additionalhour. The mixture was poured over ice-water, 1M NaOH (7 ml) was addedand the pH was adjusted to 7 with 2M HCl. The reaction was extractedwith dichloromethane (3×10 mL). The combined organics were dried withMgSO₄, filtered and evaporated to yield a residue that was purified bysilica gel chromatography eluting with 5-20% AcOEt in dichloromethane toyield7-chloro-1′-(3-methoxy-4-(trifluoromethyl)benzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde(400 mg, 77%). ESI-MS m/z calc. 504.9. found 505.3 (M+1)⁺; Retentiontime: 2.04 minutes (3 min run).1′-(4-Isopropoxy-3-methylbenzoyl)-9-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehydewas synthesized from(4-isopropoxy-3-methylphenyl)(9-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanoneusing the procedure described above.

Step 2:(7-Chloro-1-(hydroxymethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-methoxy-4-(trifluoromethyl)phenyl)methanone

7-Chloro-1′-(3-methoxy-4-(trifluoromethyl)benzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde(50 mg, 0.10 mmol) dissolved in dry THF (3 mL) was cooled to 0° C. NaBH₄(3.9 mg, 0.10 mmol) was added and stirring was continued for 30 min. Themixture was filtered through Celite, evaporated and purified by columnchromatography (5-30% AcOEt in dichloromethane) to yield(7-chloro-1-(hydroxymethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-methoxy-4-(trifluoromethyl)phenyl)methanone.ESI-MS m/z calc. 506.9. found 507.0 (M+1)⁺;Retention time: 1.96 minutes (3 min run).

7-Chloro-1′-(3-methoxy-4-(trifluoromethyl)benzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile

To a solution of7-chloro-1′-(3-methoxy-4-(trifluoromethyl)benzoyl)spiro-[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde(310 mg, 0.61 mmol) in ethanol (1.5 mL) was added an aqueous solution ofhydroxylamine hydrochloride (190 mg, 2.7 mmol) and sodium acetate (380mg, 4.6 mmol) in water (1.5 mL). The mixture was heated at 95° C. for 2hours. The reaction mixture was cooled to 25° C., water was added andthe white precipitate that formed was collected by filtration, washedthoroughly with water and dried by azeotrope with toluene. The solid wasdissolved in Ac₂O (1.1 mL, 12 mmol) and was heated at 140° C. for 3.5hours. The mixture was cooled to 25° C., poured into ice, diluted withdichloromethane (30 mL), and neutralized with NaHCO₃ (2 g). The organicphase was separated, and the aqueous phase further extracted twice withdichloromethane. The organic layers were combined, washed with brine,dried, filtered, concentrated to a yellow oil that was purified bycolumn chromatography (silica gel, 5-30% AcOEt in hexanes) to yield7-chloro-1′-(3-methoxy-4-(trifluoromethyl)benzoyl)spiro[benzo-[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile.NMR (400 MHz, CDCl₃) δ 8.06 (t, J=10.1 Hz, 1H), 7.70 (s, 1H), 7.64 (dd,J=8.6, 1.6 Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 7.10 (dd, J=8.7, 2.2 Hz,1H), 7.03 (dd, J=10.4, 6.3 Hz, 2H), 6.13 (d, J=4.0 Hz, 1H), 4.61 (s,1H), 3.96 (d, J=20.2 Hz, 3H), 3.89-3.06 (m, 3H), 2.16-1.81 (m, 4H).ESI-MS m/z calc. 501.9. found 502.0 (M+1)⁺; Retention time: 2.17 minutes(3 min run).

1′-(4-Isopropoxy-3-methylbenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-9-carbonitrilewas synthesized from1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-9-carbaldehydeusing the procedure described above.

(4-Isopropoxy-3-methylphenyl)(1H-spiro[chromeno[3,4-d]imidazole-4,4′-piperidine]-1′-yl)methanone

A mixture of 1H-spiro[chromeno[3,4-d]imidazole-4,4′-piperidine] (210 mg,0.88 mmol), 4-isopropoxy-3-methyl-benzoic acid (170 mg, 0.89 mmol),triethylamine (370 μL, 2.6 mmol), and EDCI (170 mg, 0.89 mmol) indichloromethane (5 mL) was stirred for 16 h. The reaction mixture wasdiluted with dichloromethane and was washed with 1 M HCl, saturatedsolution of NaHCO₃, and brine. The organics were dried over sodiumsulfate and evaporated to dryness. The crude product was purified bysilica gel chromatography eluting with 0-100% methanol indichloromethane to yield(4-isopropoxy-3-methylphenyl)(1H-spiro[chromeno[3,4-d]imidazole-4,4′-piperidine]-1′-yl)methanone(44 mg, 12%). ESI-MS m/z calc. 417.5. found 418.5 (M+1)⁺; Retentiontime: 1.44 minutes (3 min run).

(4-Isopropoxy-3-methylphenyl)(1-methyl-1H-spiro[chromeno[3,4-d[imidazole-4,4′-piperidine]-1′-yl)methanoneand(4-isopropoxy-3-methylphenyl)(3-methyl-3H-spiro[chromeno[3,4-d]imidazole-4,4′-piperidine]-1′-yl)methanone

(4-Isopropoxy-3-methylphenyl)(1H-spiro[chromeno[3,4-d]imidazole-4,4′-piperidine]-1′-yl)methanone(44 mg, 0.11 mmol), iodomethane (20 μL, 0.32 mmol), and potassiumcarbonate (29 mg, 0.21 mmol) were stirred in DMF (1 mL) for 16 h. Thereaction was filtered and evaporated. The crude material was purified bycolumn chromatography eluting with 0-10% methanol in dichloromethanefollowed by reverse phase HPLC (gradient: 1-99% ACN in water with formicacid as the modifier) to separate the two regioisomers. First elutingproduct: ESI-MS m/z calc. 431.5. found 432.7 (M+1)⁺; Retention time:1.51 minutes (3 min run). Second eluting product: ESI-MS m/z calc.431.5. found 432.7 (M+1)⁺; Retention time: 1.54 minutes (3 min run).

(4-Cyclopropyl-3-methoxy-phenyl)-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone

Step 1:(4-Bromo-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone

To a 100 mL round bottom flask was added 4-bromo-3-methoxy-benzoic acid(860 mg, 3.7 mmol), HATU (1.4 g, 3.7 mmol), DMF (6 mL) and triethylamine(1.4 mL, 10 mmol). The reaction mixture was allowed to stir for 10minutes. 1-Methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (860 mg,3.4 mmol) dissolved in DMF (6 mL) was added, and the mixture was allowedto stir at 25° C. After 2 h, the reaction was quenched with brine andwas extracted with ethyl acetate. The combined organic layers werewashed with brine 3 times. The combined organic layer were dried oversodium sulfate and evaporated. The residue was purified via silica gelchromatography (5-90% EtOAc:hexanes) to give(4-bromo-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanoneas white foam. ESI-MS m/z calc. 467.1. found 468.2 (M+1)⁺. Retentiontime: 3.04 minutes (4 min run).

Step 2:(4-Cyclopropyl-3-methoxy-phenyl)-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone

To a microwave vial was added(4-bromo-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(70 mg, 0.15 mmol), cyclopropylboronic acid (26 mg, 0.30 mmol), Fibrecat (49 mg, 0.0075 mmol), DMF (0.7 mL), and K₂CO₃ (150 μL of 3.0 M, 0.45mmol). The vial was purged with nitrogen and was heated at 120° C. for 2hours. The reaction was filtered and purified by HPLC (20-99%) MeOH:H₂O.ESI-MS m/z calc. 429.2. found 430.4 (M+1)⁺. Retention time: 2.95 minutes(4 min run).

(3-Methylbenzoimidazol-4-yl)-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone

Step 1:(1H-Benzo[d]imidazol-4-yl)(1-methyl-1H-spiro[chromeno[4,3-e]pyrazole-4,4′-piperidine]-1′-yl)methanone

To a solution of 1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine](211 mg, 0.830 mmol), 1H-benzimidazole-4-carboxylic acid (134 mg, 0.830mmol) and triethylamine (346 μL, 2.50 mmol) in dichloromethane (2 mL)was added HATU (314 mg, 0.830 mmol) in one portion and the mixture wasstirred for 12 hours. The reaction mixture was treated with 1M NaOH (1mL) for 10 minutes. Dichloromethane (5 mL) was added. The two layerswere separated and the aqueous layer was extracted with dichloromethane(2×5 mL). The organic layers were combined, washed with brine, driedover MgSO₄, filtered and evaporated to yield a residue that was purifiedon silica using a gradient of 0.5-30% MeOH in dichloromethane to yield(1H-benzo[d]imidazol-4-yl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone.ESI-MS m/z calc. 399.5. found 400.5 (M+1)⁺. Retention time: 1.12 minutes(4 min run).

Step 2:(3-Methylbenzoimidazol-4-yl)-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone

To a solution of(1H-benzo[d]imidazol-4-yl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(21 mg, 0.052 mmol) in dry THF (0.2 mL) under N₂ was added NaH (1.9 mg,0.079 mmol) at 0° C. After 30 min, MeI (3.3 μL, 0.052 mmol) was addedand the mixture was stirred at 0° C. for 1 h. The reaction mixture wasquenched with water and the solvent removed under vacuum to yield acrude residue that was taken up in methanol and purified by reversephase HPLC to give(3-methylbenzoimidazol-4-yl)-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone.ESI-MS m/z calc. 413.5. found 414.5 (M+1)⁺. Retention time: 1.13 minutes(3 min run).

[4-(2-Hydroxy-1,1-dimethyl-ethyl)-3-methoxy-phenyl]-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone

To a microwave vial was added difluorozinc (16 mg, 0.15 mmol) andPd(tBu₃P)₂ (7.6 mg, 0.015 mmol). The vial was capped and purged withnitrogen for 10 minutes. DMF (1 mL) was added and the reaction mixturewas allowed to stir for 10 minutes.(4-Bromo-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(140 mg, 0.30 mmol) dissolved in DMF (0.5 mL) was added followed bytrimethyl(2-methylprop-1-enoxy)silane (83 μL, 0.45 mmol). The reactionvessel was placed in an oil bath held at 80° C. for 16 hours. Thereaction mixture was filtered, quenched with brine and extracted withethyl acetate. The organic layer was dried over sodium sulfate, filteredand evaporated to dryness. The residue was dissolved in MeOH (2 mL).NaBH₄ (34 mg, 0.90 mmol) was added and the reaction mixture immediatelyturned from yellow to brown. The mixture was filtered and purified byHPLC (1-99%) MeOH:H₂O to provide[4-(2-hydroxy-1,1-dimethyl-ethyl)-3-methoxy-phenyl]-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone.ESI-MS m/z calc. 461.5. found 462.2 (M+1)⁺. Retention time: 2.73 minutes(4 min run).

1′-(4-(1-Hydroxy-2-methylpropan-2-yl)-3-methoxybenzoyl)spiro[benzo[b]pyrrolo-[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrilewas synthesized from1′-(4-bromo-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrileusing the procedures described above.

(4-Ethoxy-2-isopropoxy-phenyl)-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanoneStep 1:(4-Ethoxy-2-hydroxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone

In a vial were added 4-ethoxy-2-hydroxybenzoic acid (0.40 mmol) followedby HATU (170 mg, 0.44 mmol), DMF (0.7 mL), and triethylamine (220 μL,1.6 mmol). The mixture was stirred for 10 minutes before1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (100 mg, 0.40mmol) was added. The reaction mixture was allowed to stir at 25° C. for12 hours before it was filtered and purified by HPLC (1-99%) MeOH:H₂O toyield(4-ethoxy-2-hydroxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(53 mg, 32%). ESI-MS m/z calc. 419.5. found 420.4 (M+1)⁺. Retentiontime: 2.96 minutes (4 min run).

Step 2:(4-Ethoxy-2-isopropoxy-phenyl)-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone

To a vial containing a solution of(4-ethoxy-2-hydroxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(41 mg, 0.1 mmol) in DMF (0.8 mL) was added K₂CO₃ (69 mg, 0.5 mmol), and2-iodopropane (15 μL, 0.15 mmol). The mixture was stirred for 3 hours at25° C. The crude reaction mixture was filtered and purified by HPLC(1-99%) MeOH:H₂O to yield(4-ethoxy-2-isopropoxy-phenyl)-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(17 mg, 33%). ESI-MS m/z calc. 461.5. found 462.2 (M+1)⁺. Retentiontime: 3.16 minutes (4 min run).(2-Isopropoxy-4-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanonewas synthesized using the procedures described above. ESI-MS m/z calc.447.2. found 448.4 (M+1)⁺; Retention time: 3.03 minutes (4 min run).

[3-(Hydroxymethyl)-4-isopropoxy-phenyl]-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanoneStep 1:2-Isopropoxy-5-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzaldehyde

1-Methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (250 mg, 0.76mmol), 3-formyl-4-isopropoxy-benzoic acid (160 mg, 0.76 mmol), EDCI (160mg, 0.84 mmol), and Et₃N (430 μL, 3.1 mmol) were combined indichloromethane (7.1 mL) and the reaction mixture was stirred at roomtemperature for 48 hours. The reaction mixture was washed with a 1 M HCl(×2), a saturated aqueous solution of NaHCO₃ (×2) and a saturatedaqueous solution of NaCl. The organic layer was dried over Na₂SO₄,filtered and the solvent was evaporated under reduced pressure. Thecrude product was purified by column chromatography on silica gel (0-30%ethyl acetate in dichloromethane) to yield2-isopropoxy-5-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzaldehyde(117 mg, 34%) as a light yellow solid. ESI-MS m/z calc. 445.2. found446.3 (M+1)⁺; Retention time: 1.74 minutes (3 min run).

Step 2:[3-(Hydroxymethyl)-4-isopropoxy-phenyl]-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone

2-Isopropoxy-5-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzaldehyde(110 mg, 0.25 mmol) was dissolved in THF (3 mL) and LiBH₄ (11 mg, 0.50mmol) was added. The reaction was stirred at room temperature for 1.5 hbefore being quenched with methanol (3 mL). The reaction was neutralizedby the addition of a saturated sodium bicarbonate solution and wasextracted with ethyl acetate (3×). The combined organic layers weredried over Na₂SO₄, filtered and the solvent was evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel (0-100% ethyl acetate in hexane) to yield[3-(hydroxymethyl)-4-isopropoxy-phenyl]-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-F-yl)methanone(74 mg, 65%) as a white solid. ESI-MS m/z calc. 447.5. found 448.3(M+1)⁺. Retention time: 1.59 minutes (3 min run).

(7-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(2-hydroxyethyl)-3-methoxyphenyl)methanoneStep 1:2-(4-(7-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)-2-methoxyphenyl)acetaldehyde

To a microwave vial was added Pd(tBu₃P)₂ (128 mg, 0.250 mmol) anddifluorozinc (259 mg, 2.50 mmol). The vial was capped and purged withnitrogen for 10 minutes. DMF (1 mL) was added and the mixture wasstirred for 10 minutes. A solution of(4-bromo-3-methoxy-phenyl)-(7′-chlorospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl)methanone(244 mg, 0.500 mmol) in DMF (1.5 mL) was added followed bytrimethyl(vinyloxy)silane (581 mg, 5.00 mmol). The reaction mixture washeated at 80° C. for 1 h before it was quenched with brine and extractedwith EtOAc (3×). The combined organic layers were dried over sodiumsulfate and the solvent was removed. The crude reaction was purified bysilica gel chromatography (5%-80% ethyl acetate/hexanes) to give2-(4-(7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbon-yl)-2-methoxyphenyl)acetaldehyde.

Step 2:(7-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(2-hydroxyethyl)-3-methoxyphenyl)methanone

To2-(4-(7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbon-yl)-2-methoxyphenyl)acetaldehyde(from Step 1) was added MeOH (1 mL) followed by NaBH₄ (95 mg, 2.5 mmol)and the reaction was stirred for 30 minutes at ambient temperature.After 30 minutes, the mixture was filtered and the filtrate was purifiedby prep-HPLC (1-99% MeOH:H₂O) to give(7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]-oxazine-4,4′-piperidine]-1′-yl)(4-(2-hydroxyethyl)-3-methoxyphenyl)methanone(16 mg, 7%). ESI-MS m/z calc. 452.2. found 453.2 (M+1)⁺. Retention time:2.91 minutes (4.5 min run).(7-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-fluoro-4-(1-hydroxy-2-methylpropan-2-yl)phenyl)methanone[ESI-MS m/z calc. 468.2. found 469.4 (M+1)⁺. Retention time: 3.06minutes (4.5 min run)] and(7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(1-hydroxy-2-methylpropan-2-yl)phenyl)methanone[ESI-MS m/z calc. 450.2. found 451.2 (M+1)⁺. Retention time: 9.72minutes (15 min run)] were prepared using the procedures describedabove.

(4-(Isopropylsulfonyl)-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanoneStep 1:(4-(Isopropylthio)-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-e]pyrazole-4,4′-piperidine]-1′-yl)methanone

(4-Bromo-3-methoxy-phenyl)-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(300 mg, 0.64 mmol), propane-2-thiol (30 μL, 0.32 mmol),(5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (22mg, 0.038 mmol), palladium acetate (4.3 mg, 0.019 mmol), and sodiumcarbonate (680 mg, 6.4 mmol) were combined in 1,4-dioxane (1.3 mL). Thereaction mixture was heated at 100° C. for 4 hours. A second aliquot ofpropane-2-thiol (30 μL, 0.32 mmol) was added and the reaction mixturewas stirred for 16 hours. The crude reaction mixture was filitered andthen evaporated to dryness. The crude material was purified by columnchromatography utilizing a gradient of 0-100% ethyl acetate indichloromethane to provide a mixture of(4-(isopropylthio)-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanoneand(4-bromo-3-methoxy-phenyl)-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanon.

Step 2:(4-(Isopropylsulfonyl)-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone

(4-Isopropylsulfanyl-3-methoxy-phenyl)-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(291 mg, 0.6277 mmol) was dissolved in acetic acid (3 mL) and hydrogenperoxide (200 μL, 6.527 mmol) was added. The reaction mixture was heatedat 80° C. for 40 minutes before it was partitioned between ethyl acetate(15 mL) and water (10 mL). The organic layer was washed with a saturatedaqueous solution of sodium chloride, dried over sodium sulfate and thenpurified by column chromatography utilizing a gradient og 0-5% methanolin dichloromethane to yield(4-isopropylsulfonyl-3-methoxy-phenyl)-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(51 mg, 24%) as a white solid. ESI-MS m/z calc. 495.2. found 496.5(M+1)⁺. Retention time: 1.52 minutes (3 min run). ¹H NMR (400 MHz, DMSO)δ 7.83 (d, J=8.0 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.45 (s, 1H), 7.34 (s,1H), 7.29 (t, J=7.8 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.15-7.06 (m, 2H),4.45-4.31 (m, 1H), 4.10 (s, 3H), 3.97 (s, 3H), 3.68 (septet, J=6.7 Hz,1H), 3.59-3.22 (m, 3H), 2.10-1.82 (m, 4H), 1.17 (d, J=6.9 Hz, 6H).(4-(tert-Butylsulfonyl)-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanonewas also synthesized using the procedures described above.(4-(tert-Butylsulfonyl)-3-methylphenyl)(1-methyl-1H-spiro-[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanoneand(4-(ethylsulfonyl)-3-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanonewere synthesized from(4-bromo-3-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanoneusing the procedures described above.

7-Chloro-1′-(4-isopropoxy-3-methylbenzoyl)-N-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carboxamideStep 1:7-Chloro-1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]-pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carboxylicacid

To a solution of7-chloro-1′-(4-isopropoxy-3-methylbenzoyl)spiro-[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde(130 mg, 0.27 mmol) in acetone (1.5 mL) was added a solution ofpotassium permanganate (43 mg, 16 μL, 0.27 mmol) in water (1.5 mL) andacetone (1.5 mL) dropwise at 0° C. The mixture was allowed to stir atroom temperature for 2 h before it was concentrated onto Celite frommethanol. Column chromatography on the residue (0-20% EtOAc/CH₂Cl₂) gave7-chloro-1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]-pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carboxylicacid (13%).

Step 2:7-Chloro-1′-(4-isopropoxy-3-methylbenzoyl)-N-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carboxamide

7-Chloro-1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]-pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carboxylicacid (17 mg, 0.034 mmol), methanamine hydrochloride (2.3 mg, 0.034mmol), and Et₃N (19μL, 0.14 mmol) were taken up in dry dichloromethane(0.5 mL). HATU (13 mg, 0.034 mmol) was added and the mixture was allowedto stir for 15 min at room temperature. The mixture was purified byprep-HPLC to provide7-chloro-1′-(4-isopropoxy-3-methylbenzoyl)-N-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carboxamide.ESI-MS m/z calc. 507.2. found 508.0 (M+1)⁺. Retention time: 1.92 minutes(3 min run).

(2-Methoxy-4-(methylsulfonyl)phenyl)(1-methyl-1H-spiro[chromeno[4,3-e]pyrazole-4,4′-piperidine]-1′-yl)methanoneStep 1:(2-Methoxy-4-(methylthio)phenyl)(1-methyl-1H-spiro[chromeno[4,3-e]pyrazole-4,4′-piperidine]-1′-yl)methanone

A mixture of(4-fluoro-2-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(500 mg, 1.23 mmol) and methanethiol (172 mg, 2.45 mmol) in DMF (5 mL)was heated at 80° C. for 36 h. The reaction led to the desired productas well as O-demethylated version of the product. To the crude reactionmixture was added 3 eq of iodomethane to remethylate to the desiredproduct. The reaction mixture was washed with 1N HCl, sat. aq. NaHCO₃,and brine. The organics were dried over sodium sulfate and evaporated.The crude product was purified by column chromatography eluting with50-100% ethyl acetate in hexanes to give(2-methoxy-4-(methylthio)phenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(60%). ESI-MS m/z calc. 435.2. found 436.1 (M+1)⁺. Retention time: 1.53minutes (3 min run).

Step 2:(2-Methoxy-4-(methylsulfonyl)phenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone

A mixture of(2-methoxy-4-(methylthio)phenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone(320 mg, 0.74 mmol) and 30% hydrogen peroxide (250 μL) in acetic acid (3mL) was heated at 80° C. for 45 min. The mixture was diluted with waterand was extracted with ethyl acetate. The organics were washed with sat.aq. NaHCO₃ and brine. The organics were dried over sodium sulfate andevaporated to dryness. The crude material was purified by columnchromatography eluting with 70-100% ethyl acetate in hexanes to give(2-methoxy-4-(methylsulfonyl)phenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone.ESI-MS m/z calc. 467.2. found 468.2 (M+1)⁺. Retention time: 1.29 minutes(3 min run). ¹H NMR (400 MHz, DMSO) δ 7.76-7.70 (m, 1H), 7.63-7.41 (m,4H), 7.28 (t, J=7.7 Hz, 1H), 7.18-7.04 (m, 2H), 4.46-4.35 (m, 1H),4.14-4.05 (m, 3H), 3.98-3.90 (m, 3H), 3.53-3.36 (m, 1H), 3.28 (s, 3H),3.30-3.14 (m, 2H), 2.09-1.77 (m, 4H).(4-(Isopropylsulfonyl)-2-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanonewas also synthesized using the procedures described above.(1-Methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanonewas synthesized from(4-fluoro-3-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanoneusing the procedures described above.(4-(Isopropylsulfonyl)-2-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanonewas synthesized from(4-fluoro-2-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanoneusing the procedures above.

N,N-Dimethyl-2-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzamideStep 1:2-(1-Methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzoicacid

A mixture of methyl2-(1-methylspiro[chromeno[4,3-e]pyrazole-4,4′-piperidine]-1′-carbonyl)benzoate(500 mg, 1.17 mmol), NaOH (5.0 mL of 1.0 M, 5.0 mmol), and 1,4-dioxane(5 mL) was heated at 80° C. for 1.5 h. The mixture was cooled to rtbefore it was concentrated in vacuo. The solid residue was taken up inwater and was washed with ethyl acetate which was discarded. The aqueouslayer was acidified with 1N HCl and was extracted with ethyl acetate(2×). The combined organics were washed with brine, dried over sodiumsulfate, and were concentrated in vacuo to give2-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyebenzoicacid (33 mg, 75%) as a white solid. ESI-MS m/z calc. 403.2. found 404.2(M+1)+; Retention time: 2.31 minutes (3 min run). ¹H NMR (400 MHz, DMSO)δ 13.22 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.65(t, J=7.4 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.36 (br s, 2H), 7.28 (t,J=7.7 Hz, 1H), 7.08 (dd, J=13.8, 6.3 Hz, 2H), 4.39 (br s, 1H), 4.10 (s,3H), 3.30-3.12 (m, 2H), 2.05-1.86 (m, 4H), 1.85-1.74 (m, 1H).

Step 2:N,N-Dimethyl-2-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzamide

Et₃N (170 μL, 1.2 mmol) was added to a mixture of2-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzoicacid (100 mg, 0.25 mmol), N-methylmethanamine hydrochloride (30 mg, 0.37mmol), EDCI (48 mg, 0.25 mmol), and CH₂Cl₂ (1.5 mL) at ambienttemperature. The mixture was allowed to stir for 16 h before it wasdiluted with CH₂Cl₂ and was washed with 1N MC1. The layers wereseparated and the organic layer was washed with 1N NaOH, and then brinebefore it was dried over sodium sulfate and was concentrated in vacuo togiveN,N-dimethyl-2-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzamide(38 mg) as a white solid. ESI-MS m/z calc. 430.2. found 431.3 (M+1)⁺;Retention time: 2.24 minutes (3 min run). ¹H NMR (400 MHz, CDCl₃) δ 7.56(d, J=7.7 Hz, 1H), 7.45-7.37 (m, 3H), 7.46-7.22 (m, 2H), 7.30-7.21 (m,1H), 7.13-7.00 (m, 2H), 4.52 (d, J=13.5 Hz, 1H), 4.19 (s, 3H), 3.74-3.51(m, 2H), 3.31 (t, J=11.9 Hz, 1H), 3.09 (s, 3H), 2.94 (s, 3H), 2.24-2.02(m, J=13.9 Hz, 2H), 2.02-1.76 (m, 2H).N-isopropyl-4-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-ylcarbonyl)benzamidewas synthesized from4-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-ylcarbonyl)benzoicacid using the procedures described above.

(S)-(4-(Tetrahydrofuran-3-ylsulfonyflphenyl)(1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanoneand(R)-(4-(tetrahydrofuran-3-ylsulfonyl)phenyl)(1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone

(4-(Tetrahydrofuran-3-ylsulfonyl)phenyl)(1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanonewas subjected to chiral SFC (column: Phenomenex Lux Cellulose-2 (250×10mm), 5 μm; mobile phase: 40% IPA w/0.2% DEA, 60% CO₂; concentration: 30mg/mL in MeOH; injection volume: 20 μL; pressure: 100 bar; detectionwavelength: 254 nm) to give two peaks. For each enantiomer, the solventwas evaporated and the residue was dissolved in ethyl acetate. Thesolution was washed with aqueous 1 M hydrochloric acid (1×1 mL), asaturated aqueous solution of sodium bicarbonate (1×1 mL) and asaturated aqueous solution of sodium chloride (1×1 mL). The organiclayer was dried over sodium sulfate, filtered and the solvent wasevaporated under reduced pressure to yield[4-[(3S)-tetrahydrofuran-3-yl]sulfonylphenyl]-[1′-(trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanoneas a yellow solid (peak 1, the stereochemistry was randomly assigned):ESI-MS m/z calc. 546.1. found 547.2 (M+1)+; Retention time: 1.93 minutes(3 min run); NMR (400 MHz, DMSO) δ7.99 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.3Hz, 2H), 7.57 (d, J=8.0 Hz, 1H), 7.37-7.14 (m, 3H), 7.03 (d, J=3.9 Hz,1H), 6.40 (d, J=4.0 Hz, 1H), 4.53-4.36 (m, 1H), 4.33-4.19 (m, 1H),4.08-3.94 (m, 1H), 3.91-3.58 (m, 3H), 3.56-3.16 (m, 3H), 2.19-1.82 (m,6H) and[4[(3R)-tetrahydrofuran-3-yl]sulfonylphenyl]-[1′-(trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanoneas a yellow solid (peak 2, the stereochemistry was randomly assigned):ESI-MS m/z calc. 546.1. found 547.2 (M+1)+; Retention time: 1.93 minutes(3 min run); ¹H NMR (400 MHz, DMSO) δ 7.99 (d, J=8.3 Hz, 2H), 7.74 (d,J=8.3 Hz, 2H), 7.57 (d, J=8.2 Hz, 1H), 7.36-7.14 (m, 3H), 7.03 (d, J=3.9Hz, 1H), 6.40 (d, J=4.0 Hz, 1H), 4.54-4.36 (m, 1H), 4.33-4.17 (m, 1H),4.09-3.95 (m, 1H), 3.90-3.59 (m, 3H), 3.58-3.12 (m, 3H), 2.24-1.77 (m,6H).

7-(Hydroxymethyl)-1′-(4-(isopropylsulfonyl)benzoyl)spiro[benzo-[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile

(1-Cyano-1′-(4-(isopropylsulfonyl)benzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-yl)methylacetate (16.2 mg, 0.0297 mmol) was treated with 1M LiOH (1 mL), THF (5mL) and MeOH (1 mL). The mixture was stirred at room temperature overnight. The volatiles were removed and the residue was neutralized with1N HCl. The mixture was extracted with CH₂Cl₂ (2×). The combinedorganics were dried over sodium sulfate, filtered and concentrated underreduced pressure to give7′-(hydroxymethyl)-1-(4-isopropylsulfonylbenzoyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile(11.3 mg, 75%). ESI-MS m/z calc. 505.58. found 506.5 (M+1)+; Retentiontime 1.49 minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 7.93 (dd, J=8.2,6.5 Hz, 3H), 7.73 (d, J=8.3 Hz, 2H), 7.32 (d, J=4.0 Hz, 1H), 7.25 (s,1H), 7.15 (d, J=8.4 Hz, 1H), 6.45 (d, J=4.1 Hz, 1H), 5.39-5.30 (m, 1H),4.51 (s, 2H), 3.81-3.64 (m, 1H), 3.54-3.42 (m, 2H), 3.41-3.37 (m, 1H),2.20-2.12 (m, 1H), 2.13-2.03 (m, 1H), 2.01 (t, J=5.9 Hz, 1H), 1.57 (dd,J=12.5, 6.2 Hz, 1H), 1.17 (d, J=6.8 Hz, 6H).

Table 2 below recites the analytical data for the compounds of Table 1.

TABLE 2 Cmpd LC/MS LC/RT No. M + 1 min ¹H NMR 1 523.25 2.48 2 436.082.13 3 430.70 1.61 1H NMR (400 MHz, CDCl3) d 8.12 (d, J = 7.9 Hz, 1H),7.42 (d, J = 7.4 Hz, 1H), 7.27-7.05 (m, 4H), 7.02 (dd, J = 7.0, 4.0 Hz,1H), 6.10 (dd, J = 14.8, 3.9 Hz, 1H), 4.86-4.72 (m, 2H), 4.70-4.55 (m,1H), 3.88 (d, J = 4.8 Hz, 3H), 3.62-3.51 (m, 1H), 3.48-3.17 (m, 3H),2.32-1.87 (m, 6H), 1.78-1.62 (m, 1H). 4 432.70 1.56 5 432.30 1.96 6483.16 1.98 7 431.00 2.19 8 485.30 1.62 9 485.50 1.79 1H NMR (400 MHz,CDCl3) d 7.69-7.61 (m, 3H), 7.43 (d, J = 8.2 Hz, 2H), 7.23-7.01 (m, 3H),6.81 (d, J = 3.9 Hz, 1H), 6.06 (d, J = 3.9 Hz, 1H), 4.92 (d, J = 8.0 Hz,2H), 4.82 (d, J = 8.0 Hz, 2H), 4.66 (bs, 1H), 3.80-3.15 (m, 4H),2.32-1.67 (m, 4). 10 462.20 3.16 11 533.50 2.13 1H NMR (400 MHz, DMSO) d7.98 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.1 Hz,1H), 7.34-7.25 (m, 2H), 7.25-7.16 (m, 1H), 7.03 (d, J = 3.9 Hz, 1H),6.40 (d, J = 3.9 Hz, 1H), 4.49-4.39 (m, 1H), 3.58-3.37 (m, 3H), 3.27 (d,J = 6.5 Hz, 2H), 2.17-1.96 (m, 4H), 1.93-1.80 (m, 1H), 0.98 (d, J = 6.7Hz, 6H). 12 563.40 1.91 1H NMR (400 MHz, DMSO) d 7.88 (d, J = 8.4 Hz,2H), 7.61-7.53 (m, 3H), 7.36-7.24 (m, 2H), 7.24-7.16 (m, 1H), 7.02 (d, J= 4.0 Hz, 1H), 6.41 (d, J = 4.0 Hz, 1H), 4.55-4.34 (m, 1H), 3.62-3.38(m, 2H), 3.29-3.06 (m, 1H), 2.22-1.79 (m, 4H), 1.34 (s, 6H). 13 462.501.98 14 429.30 1.51 15 469.97 3.72 16 420.30 1.75 17 493.50 1.53 1H NMR(400 MHz, DMSO) d 8.00 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 8.2 Hz, 2H),7.73 (t, J = 5.8 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.36-7.28 (m, 3H),7.27-7.17 (m, 1H), 6.47 (d, J = 4.0 Hz, 1H), 4.76-4.64 (m, 1H),4.52-4.46 (m, 1H), 3.58-3.14 (m, 4H), 2.85-2.76 (m, 2H), 2.15-2.00 (m,3H), 1.98-1.84 (m, 1H). 18 448.34 1.83 19 534.50 1.64 20 491.14 2.03 21445.08 2.10 22 424.10 1.77 1H NMR (400 MHz, CDCl3) d 12.26, 7.52, 7.26,7.24, 7.09, 7.01, 6.99, 6.32, 6.30, 6.01, 5.97, 5.94, 4.76, 4.73, 4.65,4.61, 3.68, 3.65, 3.62, 3.51, 3.48, 3.44, 3.40, 3.37, 3.27, 3.25, 3.22,2.30, 2.26, 2.21, 2.17, 2.13, 2.07, 2.01, 1.99, 1.96, 1.91, 1.76, 1.73,1.70, 1.59, 1.25, 0.07. 23 473.30 1.83 1H NMR (400 MHz, CDCl3) d 7.66(d, J = 8.0 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.26-7.03 (m, 5H), 6.81(dd, J = 7.0, 4.1 Hz, 1H), 6.06 (dd, J = 16.3, 3.9 Hz, 1H), 4.86-4.60(m, 3H), 3.88 (s, 3H), 3.64-3.18 (m, 4H), 2.31-1.87 (m, 4H). 24 418.001.85 25 465.50 6.80 26 513.50 1.80 27 393.07 2.72 28 432.50 1.83 1H NMR(400 MHz, DMSO) d 7.74 (d, J = 7.4 Hz, 1H), 7.47 (s, 1H), 7.42-7.36 (m,2H), 7.28 (t, J = 7.4 Hz, 1H), 7.15-7.05 (m, 2H), 7.05-6.99 (m, 2H),4.44-4.13 (m, 1H), 4.10 (s, 3H), 3.72-3.39 (m, 2H), 3.31-3.17 (m, 1H),2.02-1.85 (m, 4H), 1.33 (s, 9H). 29 443.20 2.17 30 481.40 2.79 31 497.101.84 32 443.70 2.34 1H NMR (400 MHz, CDCl3) d 6.90-6.77 (m, 7H),6.68-6.52 (m, 4H), 6.34 (d, J = 8.0 Hz, 1H), 5.85 (dd, J = 5.8, 2.9 Hz,1H), 5.55 (d, J = 3.6 Hz, 1H), 4.44 (br s, 1H), 4.10 (d, J = 2.3 Hz,1H), 3.79 (br s, 1H), 2.05-1.87 (m, 4H), 1.74 (d, J = 2.2 Hz, 3H), 1.61(s, 3H), 1.11 (d, J = 2.3 Hz, 12H), 0.89 (dd, J = 6.0, 2.3 Hz, 6H). 33444.17 2.42 34 493.50 1.80 35 485.19 1.83 36 472.30 2.16 37 485.50 1.8838 435.50 2.38 39 438.50 1.70 1H NMR (400 MHz, DMSO) d 7.72, 7.70, 7.52,7.47, 7.45, 7.31, 7.31, 7.15, 7.14, 7.13, 6.30, 6.30, 6.29, 6.14, 6.13,6.10, 6.08, 5.76, 4.39, 4.35, 3.46, 3.34, 3.18, 3.14, 3.12, 2.89, 2.79,2.77, 2.75, 2.73, 2.67, 2.50, 2.33, 2.02, 1.98, 1.93, 1.90, 1.86, 1.83,1.19, 1.17, −0.00. 40 443.00 1.78 41 453.50 1.78 1H NMR (400 MHz, DMSO)d 7.87 (d, J = 2.0 Hz, 1H), 7.86-7.81 (m, 1H), 7.67 (d, J = 7.6 Hz, 1H),7.50 (s, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.22-7.02 (m, 3H), 6.28 (t, J =3.1 Hz, 1H), 6.16 (d, J = 2.3 Hz, 1H), 4.52-4.18 (m, 1H), 4.00 (s, 3H),3.58 (s, 3H), 3.28 (s, 3H), 1.98 (s, 4H). 42 446.00 1.99 1H NMR (400MHz, CDCl3) d 8.18-8.12 (m, 1H), 7.26-7.13 (m, 5H), 7.07-6.96 (m, 2H),6.15-6.10 (m, 1H), 4.61 (dt, J = 12.0, 6.0 Hz, 2H), 3.44 (s, 3H), 2.07(dt, J = 47.5, 23.6 Hz, 5H), 1.46-1.36 (m, 6H). 43 414.00 1.13 44 392.202.97 45 495.50 1.89 1H NMR (400 MHz, CDCl3) d 7.25 (d, J = 6.6 Hz, 1H),7.14-7.07 (m, 3H), 7.04-6.96 (m, 3H), 6.32 (t, J = 3.2 Hz, 1H), 6.03(dd, J = 3.5, 1.3 Hz, 1H), 5.00 (d, J = 7.6 Hz, 2H), 4.86 (d, J = 7.6Hz, 2H), 4.72-4.57 (m, 1H), 3.84 (s, 3H), 3.77-3.49 (m, 2H), 3.45-3.23(m, 1H), 3.09 (s, 3H), 2.26-1.75 (m, 4H). 46 509.00 1.67 47 462.30 2.4648 463.50 1.88 49 507.50 1.56 1H NMR (400 MHz, DMSO) d 8.00 (d, J = 8.0Hz, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.1 Hz, 3H), 7.34 (d, J= 4.0 Hz, 1H), 7.31 (d, J = 4.2 Hz, 2H), 7.28-7.18 (m, 1H), 6.47 (d, J =4.0 Hz, 1H), 4.72-4.68 (m, 1H), 4.50-4.38 (m, 1H), 3.55-3.38 (m, 2H),3.29-3.15 (m, 1H), 3.16-3.07 (m, 2H), 2.14-2.04 (m, 3H), 1.95-1.86 (m,1H), 0.90 (d, J = 6.2 Hz, 3H). 50 485.50 2.18 1H NMR (400 MHz, CDCl3) d7.67 (d, J = 8.0 Hz, 1H), 7.39 (dd, J = 21.6, 8.1 Hz, 4H), 7.20-7.05 (m,3H), 6.81 (d, J = 3.9 Hz, 1H), 6.06 (d, J = 3.9 Hz, 1H), 4.75-4.55 (m,1H), 4.44-4.40 (m, 1H), 3.81-3.20 (m, 3H), 2.28-1.72 (m, 7H), 0.98 (d, J= 6.7 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H). 51 478.30 1.62 52 435.50 1.8653 480.50 1.54 1H NMR (400 MHz, DMSO) d 7.79 (s, 1H), 7.76-7.69 (m, 2H),7.66-7.42 (m, 2H), 7.28 (t, J = 7.6 Hz, 1H), 7.17-7.03 (m, 2H),4.50-4.37 (m, 1H), 4.10 (s, 3H), 3.54-3.39 (m, 2H), 3.37-3.09 (m, 2H),2.44-2.30 (m, 3H), 2.11-1.70 (m, 4H), 1.17 (d, J = 6.8 Hz, 6H). 54458.37 1.59 1H NMR (400 MHz, CDCl3) d 8.16-8.09 (m, 1H), 7.49 (d, J =7.9 Hz, 1H), 7.25-7.18 (m, 3H), 7.17-7.11 (m, 2H), 7.02 (d, J = 4.0 Hz,1H), 6.10 (d, J = 4.0 Hz, 1H), 4.66 (s, 1H), 3.98 (d, J = 11.1 Hz, 1H),3.82-3.71 (m, 1H), 3.68 (d, J = 11.1 Hz, 1H), 3.63-3.24 (m, 2H), 2.55(s, 3H), 2.25-2.13 (m, 1H), 2.03-1.73 (m, 4H), 1.58 (s, 3H). 55 421.102.62 56 430.50 1.95 57 481.14 2.45 58 400.21 2.33 59 433.10 1.61 60427.23 2.10 61 408.20 1.66 62 444.50 2.71 63 427.50 2.07 1H NMR (400MHz, CDCl3) d 7.26 (d, J = 8.7 Hz, 1H), 7.13-7.06 (m, 4H), 7.02 (dd, J =8.5, 2.2 Hz, 1H), 6.99-6.93 (m, 1H), 6.34 (t, J = 3.2 Hz, 1H), 6.06-6.01(m, 1H), 4.61 (s, 1H), 3.92 (s, 3H), 3.73 (s, 1H), 3.49 (s, 1H), 3.36(s, 1H), 2.26-1.73 (m, 4H). 64 480.20 1.69 65 442.70 1.85 1H NMR (400MHz, CDCl3) d 8.12 (d, J = 7.1 Hz, 1H), 7.47-7.30 (m, 4H), 7.26-7.18 (m,2H), 7.17-7.07 (m, 2H), 7.01 (t, J = 5.5 Hz, 1H), 6.10 (d, J = 4.0 Hz,1H), 4.67 (m, 1H), 4.43 (m, 1H), 3.51 (m, 4H), 2.32-1.71 (m, 6H), 0.97(d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H). 66 448.50 3.26 67 494.302.33 68 501.30 2.06 69 471.19 2.83 H NMR (400.0 MHz, DMSO) d 7.76-7.65(m, 3H), 7.50-7.49 (m, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.17-7.05 (m, 3H),6.29-6.28 (m, 1H), 6.17-6.16 (m, 1H), 4.61-4.18 (m, 1H), 4.12 (t, J =6.2 Hz, 2H), 3.83-3.05 (m, 3H), 1.98 (s, 4H), 1.78-1.73 (m, 2H) and 0.99(t, J = 7.4 Hz, 3H) ppm. 70 499.30 1.88 71 441.16 2.20 72 551.50 2.20 1HNMR (400 MHz, CDCl3) d 7.59 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 2.3 Hz,1H), 7.07 (dd, J = 8.8, 2.3 Hz, 1H), 7.01 (d, J = 1.7 Hz, 1H), 6.98 (dd,J = 8.2, 1.8 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 3.9 Hz,1H), 6.06 (d, J = 3.9 Hz, 1H), 4.22-4.15 (m, 3H), 3.88 (s, 3H),3.81-3.76 (m, 2H), 3.44 (s, 3H), 3.53-3.30 (m, 3H), 2.18-1.80 (m, 4H).73 501.23 2.14 74 477.30 2.04 75 495.20 2.01 76 400.50 1.68 1H NMR (400MHz, DMSO) d 9.75 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 3.7Hz, 1H), 7.31 (d, J = 4.1 Hz, 2H), 7.26-7.21 (m, 1H), 7.20 (s, 1H), 7.13(d, J = 8.1 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.49 (d, J = 3.9 Hz, 1H),3.08 (s, 1H), 2.13 (s, 3H), 2.05-1.91 (m, 4H). 77 376.26 1.95 78 534.301.99 1H NMR (400 MHz, CDCl3) d 7.96 (d, J = 8.2 Hz, 2H), 7.87 (dd, J =7.6, 1.4 Hz, 1H), 7.64-7.58 (m, 3H), 7.37-7.29 (m, 1H), 7.13-7.01 (m,2H), 4.67 (d, J = 12.7 Hz, 1H), 3.75-3.58 (m, 1H), 3.58-3.49 (m, 1H),3.47-3.33 (m, 1H), 2.32 (d, J = 12.4 Hz, 1H), 2.21-2.07 (m, 1H),2.03-1.84 (m, 1H), 1.84-1.64 (m, 1H), 1.36 (s, 9H). 79 400.21 2.13 80424.16 1.71 81 409.11 2.01 82 490.30 2.07 83 463.10 1.65 84 458.25 1.8785 491.19 2.04 86 427.25 2.27 87 391.24 1.79 88 426.24 1.77 89 461.222.22 90 499.50 4.71 91 476.30 2.12 92 414.50 1.36 93 468.20 1.29 1H NMR(400 MHz, DMSO) d 7.76-7.70 (m, 1H), 7.63-7.41 (m, 4H), 7.28 (t, J = 7.7Hz, 1H), 7.18-7.04 (m, 2H), 4.46-4.35 (m, 1H), 4.14-4.05 (m, 3H),3.98-3.90 (m, 3H), 3.53-3.36 (m, 1H), 3.28 (s, 3H), 3.30-3.14 (m, 2H),2.09-1.77 (m, 4H). 94 462.20 1.71 1H NMR (400 MHz, DMSO) d 7.73 (d, J =7.7 Hz, 1H), 7.44 (d, J = 12.9 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H),7.22-7.01 (m, 3H), 6.67-6.56 (m, 2H), 4.39 (d, J = 12.8 Hz, 1H), 4.09(s, 3H), 3.79 (s, 3H), 3.50-3.34 (m, 1H), 3.31-3.11 (m, 2H), 2.07-1.93(m, 1H), 1.93-1.72 (m, 3H), 1.34 (s, 9H). 95 501.30 2.53 96 441.16 2.2897 435.10 1.37 98 434.20 1.55 99 400.20 0.71 1H NMR (400 MHz, DMSO) d8.62 (d, J = 6.8 Hz, 1H), 8.03 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.64(s, 1H), 7.45 (s, 1H), 7.28 (t, J = 7.6 Hz, 2H), 7.13 (d, J = 8.1 Hz,1H), 7.07 (t, J = 7.6 Hz, 1H), 6.96 (t, J = 6.8 Hz, 1H), 4.46 (d, J =13.1 Hz, 1H), 4.10 (s, 3H), 3.52-3.13 (m, 3H), 2.13-1.75 (m, 4H). 100438.50 1.36 101 458.34 1.64 1H NMR (400 MHz, CDCl3) d 8.12 (d, J = 8.2Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.21 (dd, J = 11.1, 4.2 Hz, 1H), 7.12(dd, J = 13.0, 5.0 Hz, 2H), 7.01 (d, J = 4.0 Hz, 1H), 6.99 (d, J = 8.4Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.12 (d, J = 4.0 Hz, 1H), 4.61 (d, J= 13.2 Hz, 1H), 3.88 (d, J = 1.0 Hz, 6H), 3.52 (s, 2H), 3.25 (t, J =11.9 Hz, 1H), 2.15 (d, J = 14.1 Hz, 1H), 2.07 (s, 1H), 1.96 (t, J = 12.6Hz, 2H), 1.64 (s, 1H). 102 376.15 1.42 103 469.40 3.06 104 444.24 2.10105 407.40 3.18 106 451.20 9.72 107 477.14 2.03 108 478.30 1.92 1H NMR(400 MHz, CDCl3) d 7.52, 7.49, 7.47, 7.33, 7.31, 7.29, 7.29, 7.27, 7.26,7.26, 7.23, 7.21, 7.19, 7.16, 7.14, 7.08, 7.04, 7.02, 6.99, 6.83, 6.64,6.46, 5.30, 4.69, 4.66, 4.13, 3.99, 3.61, 3.58, 3.54, 3.51, 3.40, 3.36,3.33, 3.30, 3.27, 2.20, 2.17, 2.07, 2.04, 2.01, 1.97, 1.96, 1.94, 1.93,1.91, 1.90, 1.76, 1.62, 1.57, 1.52. 109 404.30 2.33 110 430.27 2.43 111423.24 2.07 112 461.50 2.68 113 411.20 1.45 114 475.30 1.78 115 418.001.83 116 493.25 2.19 117 436.50 1.80 118 457.23 2.52 119 452.30 1.16 1HNMR (400 MHz, DMSO) d 7.97 (s, 1H), 7.95-7.89 (m, 2H), 7.77-7.68 (m,3H), 7.26-7.21 (m, 2H), 7.19-7.12 (m, 2H), 4.36-4.23 (m, 1H), 3.59-3.40(m, 4H), 2.18-2.00 (m, 3H), 1.99-1.87 (m, 1H), 1.17 (d, J = 6.8 Hz, 6H).120 438.50 1.73 1H NMR (400 MHz, CDCl3) d 7.54, 7.44, 7.42, 7.30, 7.28,7.28, 7.23, 7.13, 7.12, 7.12, 7.06, 7.05, 7.04, 7.03, 7.02, 6.55, 6.55,6.37, 6.36, 6.36, 6.28, 6.28, 6.26, 6.26, 6.06, 6.05, 5.32, 5.30, 5.29,5.27, 5.25, 5.23, 4.62, 4.59, 3.76, 3.72, 3.63, 3.60, 3.57, 3.52, 3.51,3.32, 3.28, 3.25, 2.22, 2.19, 2.12, 2.08, 2.03, 2.03, 1.98, 1.95, 1.91,1.88, 1.65, 1.60, 1.55, 1.53, 1.39, 1.38, 1.23, 1.22, 0.98. 121 474.281.81 122 544.24 2.13 123 505.10 2.06 1H NMR (400 MHz, DMSO) d 7.96 (d, J= 7.9 Hz, 1H), 7.62-7.49 (m, 3H), 7.35-7.25 (m, 2H), 7.25-7.17 (m, 1H),7.03 (d, J = 3.9 Hz, 1H), 6.41 (d, J = 4.0 Hz, 1H), 4.51-4.36 (m, 1H),3.58-3.14 (m, 3H), 3.25 (s, 3H), 2.68 (s, 3H), 2.19-1.81 (m, 4H). 124388.27 1.77 125 454.50 1.98 1H NMR (400 MHz, CDCl3) d 8.14, 8.12, 8.02,7.52, 7.31, 7.26, 7.24, 7.21, 7.19, 7.16, 7.14, 7.12, 7.03, 7.02, 6.81,6.62, 6.44, 6.12, 6.11, 4.71, 3.97, 3.59, 3.56, 3.54, 3.50, 3.48, 3.42,3.40, 3.33, 3.29, 3.26, 3.23, 2.96, 2.88, 2.80, 2.21, 2.18, 2.14, 2.10,2.06, 2.02, 1.97, 1.77, 1.57, 0.94. 126 485.16 2.32 127 426.30 1.83 128418.30 2.44 129 477.26 2.16 130 458.50 2.11 131 485.16 2.33 132 475.301.87 133 515.24 2.28 134 501.30 2.06 135 452.50 1.93 136 441.16 2.50 137432.50 1.46 138 453.28 2.18 139 483.30 1.40 140 465.50 4.00 141 452.301.46 1H NMR (400 MHz, DMSO) d 7.96 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 7.7Hz, 1H), 7.56-7.50 (m, 2H), 7.46 (s, 1H), 7.29 (t, J = 7.7 Hz, 1H),7.15-7.05 (m, 2H), 4.44-4.32 (m, 1H), 4.10 (s, 3H), 3.61-3.36 (m, 2H),3.26 (s, 3H), 2.68 (s, 3H), 2.11-1.81 (m, 5H). 142 465.40 3.02 143458.10 2.66 144 462.19 2.11 145 442.18 2.57 146 478.30 2.22 147 410.501.55 1H NMR (400 MHz, CDCl3) d 7.42, 7.42, 7.40, 7.40, 7.24, 7.24, 7.23,7.22, 7.17, 7.12, 7.11, 7.09, 7.04, 6.94, 6.93, 6.86, 6.86, 6.84, 6.84,6.73, 6.38, 6.30, 6.18, 6.17, 6.16, 6.11, 6.09, 6.07, 5.92, 5.91, 5.70,4.51, 4.47, 3.60, 3.42, 3.37, 3.33, 3.29, 3.25, 3.17, 3.14, 3.11, 2.89,2.47, 2.02, 1.99, 1.94, 1.93, 1.89, 1.86, 1.62, 1.11, 1.08, 0.73, 0.71,0.49, 0.47, 0.45, −0.00. 148 447.15 2.25 149 487.30 1.93 150 445.30 2.021H NMR (400 MHz, CDCl3) d 7.80 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 7.8 Hz,1H), 7.51 (d, J = 8.0 Hz, 2H), 7.32-7.22 (m, 2H), 7.10-7.00 (m, 2H),5.92 (d, J = 6.7 Hz, 1H), 4.61 (d, J = 10.7 Hz, 1H), 4.29 (dq, J = 13.5,6.6 Hz, 1H), 4.17 (s, 3H), 3.58 (s, 2H), 3.38 (t, J = 12.4 Hz, 1H),2.29-2.13 (m, 1H), 2.08-1.90 (m, 1H), 1.78 (s, 1H), 1.28 (d, J = 6.5 Hz,7H). 151 547.20 1.93 1H NMR (400 MHz, DMSO) d 7.99 (d, J = 8.4 Hz, 2H),7.74 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.37-7.14 (m, 3H),7.03 (d, J = 3.9 Hz, 1H), 6.40 (d, J = 4.0 Hz, 1H), 4.53-4.36 (m, 1H),4.33-4.19 (m, 1H), 4.08-3.94 (m, 1H), 3.91-3.58 (m, 3H), 3.56-3.16 (m,3H), 2.19-1.82 (m, 6H). 152 445.15 2.43 153 418.50 1.62 1H NMR (400 MHz,CDCl3) d 7.38 (s, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.28-7.22 (m, 2H),7.22-7.06 (m, 4H), 6.82 (d, J = 9.0 Hz, 1H), 4.56 (sept, J = 5.8 Hz,1H), 4.43-3.76 (m, 2H), 3.65-3.37 (m, 2H), 2.36-2.15 (m, 2H), 2.21 (s,3H), 2.14-2.00 (m, 2H), 1.33 (t, J = 10.2 Hz, 6H). 154 422.50 1.74 1HNMR (400 MHz, CDCl3) d 7.51, 7.49, 7.29, 7.28, 7.26, 7.14, 7.12, 7.11,7.09, 7.07, 7.05, 7.03, 7.01, 7.00, 5.30, 4.67, 4.50, 4.48, 4.46, 4.44,3.99, 3.99, 3.64, 3.61, 3.57, 3.53, 3.50, 3.39, 3.35, 3.33, 3.29, 2.22,2.19, 2.03, 1.96, 1.92, 1.89, 1.77, 1.73, 1.57, 1.54, 1.52, 1.23, 1.21.155 444.24 1.86 156 458.00 1.89 1H NMR (400 MHz, CDCl3) d 8.15 (d, J =7.9 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.20-7.12 (m, 2H), 7.04 (d, J =3.2 Hz, 2H), 6.99 (dd, J = 8.2, 1.5 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H),6.12 (d, J = 4.0 Hz, 1H), 4.59 (dt, J = 12.2, 6.1 Hz, 2H), 3.89 (s, 3H),3.57 (d, J = 110.2 Hz, 2H), 2.82 (s, 3H), 2.38-1.77 (m, 5H), 1.40 (d, J= 6.0 Hz, 6H). 157 427.20 2.21 158 432.00 1.83 1H NMR (400 MHz, CDCl3) d7.56 (d, J = 7.7 Hz, 1H), 7.33-6.98 (m, 5H), 6.73 (d, J = 9.0 Hz, 2H),4.65 (d, J = 12.8 Hz, 1H), 4.55 (dt, J = 12.1, 6.1 Hz, 1H), 4.14 (s,3H), 3.62-3.24 (m, 3H), 2.32 (s, 3H), 2.26-1.60 (m, 5H), 1.32 (d, J =6.0 Hz, 6H). 159 373.20 2.99 160 402.50 1.76 161 457.50 2.19 162 416.212.31 163 411.20 2.08 164 503.30 2.06 1H NMR (400 MHz, DMSO) ? 7.57 (d, J= 8.2 Hz, 1H), 7.38-7.24 (m, 2H), 7.24-7.17 (m, 1H), 6.98 (t, J = 22.1Hz, 2H), 6.84 (d, J = 8.6 Hz, 1H), 6.40 (s, 1H), 4.46 (d, J = 12.7 Hz,1H), 3.81 (d, J = 6.3 Hz, 6H), 3.75 (s, 3H), 3.36 (s, 2H), 3.15 (s, 1H),1.94 (dd, J = 33.5, 13.8 Hz, 4H). 165 462.50 3.04 166 449.50 2.14 167440.50 1.78 1H NMR (400 MHz, CDCl3) d 7.51, 7.49, 7.43, 7.42, 7.40,7.38, 7.36, 7.31, 7.29, 7.27, 7.26, 7.24, 7.21, 7.19, 7.12, 7.10, 7.07,7.05, 7.03, 7.00, 6.76, 6.58, 6.56, 6.39, 4.66, 4.50, 4.48, 4.46, 4.44,3.62, 3.59, 3.55, 3.52, 3.49, 3.47, 3.45, 3.38, 3.33, 3.29, 2.18, 2.07,2.04, 2.01, 1.97, 1.93, 1.91, 1.80, 1.76, 1.62, 1.60, 1.57, 1.54, 1.52,1.23, 1.21, 1.19. 168 451.10 1.65 1H NMR (400 MHz, DMSO) d 7.71 (dd, J =8.9, 5.6 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.50 (dd, J = 2.9, 1.4 Hz,1H), 7.11 (dd, J = 9.6, 2.8 Hz, 1H), 7.03-6.89 (m, 3H), 6.28 (t, J = 3.2Hz, 1H), 6.19 (dd, J = 3.4, 1.4 Hz, 1H), 4.53-4.24 (m, 1H), 3.83 (s,3H), 3.71-3.36 (m, 3H), 2.05-1.83 (m, 4H), 1.48 (s, 6H). 169 456.50 1.711H NMR (400 MHz, DMSO) d 7.74 (d, J = 7.7 Hz, 1H), 7.46 (s, 1H),7.35-6.92 (m, 7H), 4.43-4.29 (m, 1H), 4.10 (s, 3H), 3.87 (s, 3H),3.65-3.19 (m, 3H), 2.11-1.80 (m, 4H). 170 499.30 7.77 171 459.50 1.99172 497.21 2.04 173 417.02 2.57 174 446.30 2.61 175 462.30 1.81 176516.00 1.79 177 415.19 2.05 178 528.26 2.45 179 445.15 2.42 180 466.501.61 181 457.50 2.15 182 430.70 1.75 183 469.50 1.78 184 405.50 4.54 1HNMR (400 MHz, DMSO) d 7.66 (dd, J = 7.6, 1.4 Hz, 1H), 7.55-7.46 (m, 1H),7.42 (d, J = 8.7 Hz, 2H), 7.23-7.05 (m, 3H), 6.98 (d, J = 8.7 Hz, 2H),6.28 (t, J = 3.2 Hz, 1H), 6.22-6.14 (m, 1H), 4.93-4.81 (m, 1H),4.50-4.06 (m, 1H), 4.03 (t, J = 12.1, 7.2 Hz, 2H), 3.77-3.67 (m, 2H),3.56-3.06 (m, 3H), 2.07-1.78 (m, 4H). 185 446.08 2.33 186 399.23 2.13187 420.30 1.55 188 432.20 1.76 189 439.14 2.03 190 448.30 2.35 191503.30 2.06 192 423.20 2.18 193 465.50 2.27 194 444.50 1.73 1H NMR (400MHz, CDCl3) d 7.58, 7.56, 7.52, 7.32, 7.31, 7.30, 7.29, 7.28, 7.26,7.23, 7.21, 7.19, 7.16, 7.14, 7.10, 7.07, 7.05, 7.03, 7.00, 6.84, 6.64,6.46, 6.10, 4.68, 4.65, 4.16, 3.99, 3.64, 3.60, 3.58, 3.55, 3.49, 3.47,3.39, 3.36, 3.33, 3.30, 2.22, 2.19, 2.06, 1.97, 1.93, 1.90, 1.75, 1.62,1.57, 1.53, 1.52, 1.25, 1.23, 1.21, 1.19. 195 489.30 1.70 196 493.501.74 197 430.50 4.47 1H NMR (400 MHz, DMSO) d 8.00 (d, J = 7.9 Hz, 1H),7.42 (d, J = 8.6 Hz, 2H), 7.32 (dd, J = 10.2, 4.1 Hz, 3H), 7.28-7.17 (m,1H), 6.99 (d, J = 8.6 Hz, 2H), 6.48 (d, J = 4.0 Hz, 1H), 4.88 (t, J =5.5 Hz, 1H), 4.58-4.08 (m, 1H), 4.03 (t, J = 4.9 Hz, 2H), 3.72 (q, J =10.1, 5.2 Hz, 2H), 3.67-3.09 (m, 3H), 2.15-1.80 (m, 4H). 198 510.50 2.31199 200 421.30 2.58 201 365.25 1.95 202 446.50 6.06 1H NMR (400 MHz,DMSO) d 7.73 (d, J = 6.8 Hz, 1H), 7.48 (s, 1H), 7.28 (t, J = 7.3 Hz,1H), 7.16-6.88 (m, 3H), 6.83 (s, 1H), 4.66-4.50 (m, 1H), 4.39 (d, J =12.4 Hz, 1H), 4.09 (s, 3H), 3.42 (d, J = 12.2 Hz, 1H), 3.33 (s, 5H),2.20 (s, 3H), 2.09 (s, 3H), 1.90 (dd, J = 32.3, 19.2 Hz, 4H), 1.27 (d, J= 6.0 Hz, 6H). 203 463.50 1.87 204 509.21 2.04 205 448.40 3.03 206416.50 2.03 1H NMR (400 MHz, DMSO) d 9.43 (s, 1H), 8.00 (d, J = 7.9 Hz,1H), 7.34 (s, 1H), 7.31 (d, J = 4.0 Hz, 2H), 7.26-7.21 (m, 1H), 7.00 (d,J = 1.8 Hz, 1H), 6.91 (dd, J = 8.1, 1.9 Hz, 1H), 6.80 (d, J = 8.1 Hz,1H), 6.48 (d, J = 4.1 Hz, 1H), 5.76 (s, 1H), 3.79 (s, 3H), 3.50-3.38 (m,1H), 3.30-3.17 (m, 1H), 2.09-1.92 (m, 4H). 207 539.50 1.95 208 428.501.97 209 464.30 1.72 1H NMR (400 MHz, DMSO) d 8.02 (s, 1H), 7.87 (d, J =8.3 Hz, 2H), 7.72-7.64 (m, 3H), 7.53-7.46 (m, 1H), 7.20-7.03 (m, 3H),6.32-6.26 (m, 1H), 6.20-6.15 (m, 1H), 4.58-4.27 (m, 1H), 3.64-3.14 (m,3H), 2.15-1.83 (m, 5H), 0.55-0.33 (m, 4H). 210 491.36 2.63 211 467.301.72 212 404.30 1.84 213 466.50 2.24 214 442.50 1.91 215 402.10 2.17 216467.10 1.77 217 374.20 2.93 218 413.27 2.28 219 404.40 2.86 220 460.502.27 1H NMR (400 MHz, CDCl3) d 7.75 (d, J = 1.7, 1H), 7.60-7.51 (m, 2H),7.27 (d, J = 8.5, 1H), 7.11 (d, J = 2.1, 2H), 7.02 (dd, J = 8.5, 2.2,1H), 6.35 (t, J = 3.2, 1H), 6.05 (dd, J = 3.5, 1.3, 1H), 4.70-4.53 (m,1H), 3.72-3.51 (m, 2H), 3.44-3.23 (m, 1H), 2.28-1.77 (m, 4H), 1.53 (s,9H). 221 389.50 2.00 222 407.28 2.20 223 517.20 2.34 1H NMR (400 MHz,CDCl3) d 7.67 (d, J = 8.1 Hz, 1H), 7.22-7.06 (m, 3H), 7.01 (d, J = 1.7Hz, 1H), 6.98 (dd, J = 8.2, 1.7 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.81(d, J = 3.9 Hz, 1H), 6.05 (d, J = 3.9 Hz, 1H), 4.65-4.25 (m, 1H),4.23-4.14 (m, 2H), 3.88 (s, 3H), 3.82-3.75 (m, 2H), 3.58-3.32 (m, 3H),3.44 (s, 3H), 2.20-1.80 (m, 4H). 224 415.50 1.47 225 424.10 1.72 226411.30 1.20 227 424.10 1.73 228 523.70 6.06 229 399.23 2.25 230 418.501.40 231 486.48 1.57 1H NMR (400 MHz, DMSO) d 7.57 (d, J = 7.9 Hz, 1H),7.52 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.29 (q, J = 8.1 Hz,2H), 7.20 (t, J = 6.7 Hz, 1H), 7.02 (d, J = 4.3 Hz, 1H), 6.42 (d, J =3.9 Hz, 1H), 4.98 (s, 1H), 4.72 (t, J = 5.7 Hz, 1H), 4.51-4.31 (m, 1H),3.42 (s, 2H), 1.99 (s, 5H), 1.39 (s, 3H). 232 427.20 2.20 233 495.302.32 234 481.50 1.88 235 506.30 1.59 236 404.50 1.86 237 501.30 3.00 238535.22 2.28 1H NMR (400 MHz, DMSO) d 7.80-7.67 (m, 3H), 7.56-7.47 (m,1H), 7.37-7.26 (m, 2H), 7.14 (dd, J = 8.5, 2.3 Hz, 1H), 6.30 (t, J = 3.2Hz, 1H), 6.23-6.14 (m, 1H), 4.76-4.06 (m, 3H), 3.82-3.40 (m, 5H), 3.23(s, 3H), 2.13-1.83 (m, 6H). 239 403.18 2.79 240 450.30 1.45 241 345.501.84 242 396.00 2.91 243 479.30 1.53 1H NMR (400 MHz, DMSO) d 8.02 (s,1H), 7.87 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 7.7 Hz, 1H), 7.69 (d, J =8.2 Hz, 2H), 7.52-7.42 (m, 1H), 7.34-7.25 (m, 1H), 7.16-7.02 (m, 2H),4.47-4.29 (m, 1H), 4.10 (s, 3H), 3.60-3.22 (m, 3H), 2.15-1.80 (m, 5H),0.53-0.33 (m, 4H). 244 506.24 2.45 245 508.00 1.92 246 436.50 1.81 247433.30 1.92 1H NMR (400 MHz, DMSO) d 7.67 (d, J = 7.6 Hz, 1H), 7.56-7.43(m, 1H), 7.19-7.04 (m, 3H), 7.04-6.96 (m, 3H), 6.28 (t, J = 3.1 Hz, 1H),6.22-6.10 (m, 1H), 4.64-4.53 (m, 1H), 4.52-3.92 (m, 1H), 3.77 (s, 3H),3.61-3.09 (m, 3H), 1.96 (s, 4H), 1.26 (d, J = 6.0 Hz, 6H). 248 509.201.72 249 461.00 1.92 1H NMR (400 MHz, DMSO) d 7.83-7.64 (m, 3H),7.53-7.46 (m, 1H), 7.33 (d, J = 8.7 Hz, 1H), 7.10 (dd, J = 9.6, 2.7 Hz,1H), 7.00-6.88 (m, 1H), 6.28 (t, J = 3.1 Hz, 1H), 6.19-6.13 (m, 1H),4.58-4.16 (m, 1H), 3.94 (s, 3H), 3.56 (s, 3H), 2.05-1.79 (m, 4H). 250478.10 1.83 1H NMR (400 MHz, CDCl3) d 7.61, 7.59, 7.52, 7.43, 7.38,7.36, 7.31, 7.26, 7.15, 7.14, 7.10, 7.09, 7.07, 7.07, 7.04, 6.99, 6.83,6.82, 6.54, 6.39, 6.34, 6.23, 6.20, 6.18, 6.07, 6.06, 6.03, 4.61, 4.58,3.72, 3.69, 3.56, 3.49, 3.38, 3.25, 3.22, 3.19, 2.80, 2.19, 2.15, 2.07,2.04, 2.01, 1.96, 1.89, 1.87, 1.59, 1.36, 1.25, 0.97. 251 418.20 1.89252 440.19 2.18 253 480.30 2.25 254 389.50 5.76 255 419.30 1.64 256448.50 1.70 1H NMR (400 MHz, DMSO) d 7.74 (d, J = 7.7 Hz, 1H), 7.47 (d,J = 0.5 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.15-6.96 (m, 5H), 4.60(hept, J = 5.9 Hz, 1H), 4.51-4.05 (m, 1H), 4.10 (s, 3H), 3.78 (s, 3H),3.59-3.20 (m, 3H), 2.10-1.75 (m, 4H), 1.26 (d, J = 5.7 Hz, 6H). 257435.50 2.21 1H NMR (400 MHz, CDCl3) d 7.31-7.24 (m, 1H), 7.21 (dd, J =7.5, 1.2 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.07-6.98 (m, 4H), 4.93-4.36(m, 1H), 3.90 (s, 3H), 3.68-3.13 (m, 3H), 2.98 (s, 3H), 2.65 (q, J = 7.5Hz, 2H), 2.27-1.98 (m, 4H), 1.19 (t, J = 7.5 Hz, 3H). 258 444.20 2.21259 404.50 1.85 260 501.00 1.82 261 453.30 3.01 262 433.20 1.70 1H NMR(400 MHz, DMSO) d 7.76 (s, 1H), 7.59 (dd, J = 7.6, 1.6 Hz, 1H), 7.46 (s,2H), 7.25-7.17 (m, 1H), 7.06-6.96 (m, 2H), 4.69 (dt, J = 12.1, 6.0 Hz,1H), 4.31 (d, J = 12.7 Hz, 1H), 3.86 (s, 3H), 3.54 (s, 1H), 3.33 (t, J =11.1 Hz, 1H), 2.35 (s, 3H), 2.09-1.99 (m, 2H), 1.90 (d, J = 11.2 Hz,3H), 1.31 (d, J = 6.0 Hz, 7H). 263 499.30 7.77 264 359.00 1.95 265479.00 2.06 266 481.50 1.91 1H NMR (400 MHz, DMSO) d 7.87 (d, J = 2.2Hz, 1H), 7.78 (dd, J = 8.6, 2.2 Hz, 1H), 7.67 (dd, J = 7.6, 1.6 Hz, 1H),7.50 (dd, J = 2.9, 1.3 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.20-7.03 (m,3H), 6.28 (t, J = 3.2 Hz, 1H), 6.16 (dd, J = 3.4, 1.3 Hz, 1H), 5.03-4.85(m, 1H), 4.57-4.05 (m, 1H), 3.80-3.37 (m, 3H), 3.28 (s, 3H), 2.06-1.83(m, 4H), 1.36 (d, J = 6.0 Hz, 6H). 267 464.50 2.13 1H NMR (400 MHz,DMSO) d 7.53 (s, 1H), 7.48 (dd, J = 9.5, 2.5 Hz, 1H), 7.28-7.23 (m, 2H),7.19-7.10 (m, 2H), 7.00-6.95 (m, 1H), 4.64 (sept, J = 6.0 Hz, 1H), 4.45(q, J = 7.2 Hz, 2H), 4.34-4.10 (m, 1H), 3.87-3.39 (m, 2H), 3.32-3.08 (m,1H), 2.15 (s, 3H), 2.00-1.83 (m, 4H), 1.37 (t, J = 7.2 Hz, 3H), 1.29 (d,J = 6.0 Hz, 6H). 268 431.15 2.18 269 505.30 2.68 270 517.50 1.98 1H NMR(400 MHz, DMSO) d 7.97 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H),7.58 (d, J = 8.1 Hz, 1H), 7.34-7.25 (m, 2H), 7.25-7.17 (m, 1H), 7.03 (d,J = 3.9 Hz, 1H), 6.40 (d, J = 3.9 Hz, 1H), 4.52-4.37 (m, 1H), 3.61-3.38(m, 2H), 3.29-3.13 (m, 1H), 2.97-2.86 (m, 1H), 2.18-1.98 (m, 3H),1.95-1.84 (m, 1H), 1.19-1.11 (m, 2H), 1.11-1.01 (m, 2H). 271 433.50 1.25272 404.50 1.98 1H NMR (400 MHz, CDCl3) d 7.73 (dd, J = 17.9, 8.3 Hz,3H), 7.58 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 7.3 Hz, 2H), 7.13 (d, J =1.7 Hz, 2H), 7.05 (dd, J = 8.5, 1.9 Hz, 1H), 6.37 (t, J = 3.1 Hz, 1H),6.10-6.03 (m, 1H), 4.65 (br s, 1H), 3.60 (br s, 2H), 3.36 (br s, 1H),2.22 (br s, 1H), 2.07 (br s, 2H), 1.88 (br s, 1H), 1.62 (d, J = 2.4 Hz,3H). 273 437.26 2.35 274 446.30 2.60 1H NMR (400 MHz, CDCl3) d 7.54 (dt,J = 3.0, 1.3 Hz, 1H), 7.31-7.20 (m, 3H), 7.10-6.95 (m, 2H), 6.83 (d, J =8.2 Hz, 1H), 4.65 (br s, 1H), 4.56 (sept, J = 6.0 Hz, 1H), 4.08 (s, 3H),3.70-3.21 (m, 3H), 2.30 (s, 3H), 2.21 (s, 3H), 2.17-1.82 (m, 4H), 1.35(d, J = 1.1 Hz, 3H), 1.34 (d, J = 1.1 Hz, 3H). 275 397.50 2.07 1H NMR(400 MHz, CDCl3) d 7.46-7.37 (m, 1H), 7.30-7.27 (m, 4H), 7.25-7.10 (m,5H), 7.04 (dd, J = 8.5, 2.2 Hz, 1H), 6.36 (t, J = 3.2 Hz, 1H), 6.07 (d,J = 3.2 Hz, 1H), 4.65 (br. s, 1H), 3.57 (br. dd, J = 43.9, 16.6 Hz, 2H),3.35 (br. s, 1H), 2.20 (br. s, 1H), 2.06 (br. s, 2H), 1.87 (br. s, 1H),1.59 (s, 6H). 276 448.10 1.54 277 447.15 2.32 278 502.50 1.97 279 547.201.93 1H NMR (400 MHz, DMSO) d 7.99 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.3Hz, 2H), 7.57 (d, J = 8.2 Hz, 1H), 7.36-7.14 (m, 3H), 7.03 (d, J = 3.9Hz, 1H), 6.40 (d, J = 4.0 Hz, 1H), 4.54-4.36 (m, 1H), 4.33-4.17 (m, 1H),4.09-3.95 (m, 1H), 3.90-3.59 (m, 3H), 3.58-3.12 (m, 3H), 2.24-1.77 (m,6H). 280 444.10 2.40 281 448.50 1.70 1H NMR (400 MHz, DMSO) d 7.74 (s,1H), 7.61-7.56 (m, 1H), 7.20 (td, J = 8.2, 1.5 Hz, 1H), 7.05-6.94 (m,5H), 4.60 (hept, J = 5.6 Hz, 1H), 4.21 (s, 1H), 3.87 (s, 3H), 3.78 (s,3H), 3.60-3.32 (m, 3H), 2.06-1.78 (m, 4H), 1.26 (d, J = 6.0 Hz, 6H). 282499.30 1.84 283 460.20 2.51 284 426.30 1.67 285 436.00 1.86 1H NMR (400MHz, CDCl3) d 8.15 (d, J = 7.9 Hz, 1H), 7.39 (ddd, J = 31.5, 15.1, 7.3Hz, 3H), 7.19 (dt, J = 14.9, 8.2 Hz, 4H), 7.05 (d, J = 3.7 Hz, 1H), 6.76(s, 0H), 6.58 (d, J = 7.0 Hz, 1H), 6.39 (s, 0H), 6.13 (d, J = 3.8 Hz,1H), 4.76 (d, J = 10.5 Hz, 1H), 3.69-3.17 (m, 3H), 2.32-1.91 (m, 5H).286 495.00 1.47 287 481.50 1.71 1H NMR (400 MHz, CDCl3) d 7.34-7.23 (m,2H), 7.14-7.08 (m, 2H), 7.07-6.99 (m, 3H), 6.34 (t, J = 3.2 Hz, 1H),6.04 (dd, J = 3.5, 1.3 Hz, 1H), 5.02 (d, J = 7.2 Hz, 2H), 4.87 (d, J =7.2 Hz, 2H), 4.75-4.51 (m, 1H), 3.91 (s, 3H), 3.82-3.43 (m, 3H),2.29-1.72 (m, 4H). 288 487.27 2.04 289 462.50 1.93 1H NMR (400 MHz,CDCl3) d 7.02 (dd, J = 8.6, 1.6 Hz, 1H), 6.83-6.78 (m, 4H), 6.37 (d, J =8.1 Hz, 1H), 6.21-6.14 (m, 2H), 4.12 (dt, J = 16.6, 6.0 Hz, 1H), 3.67(t, J = 2.5 Hz, 3H), 3.38 (t, J = 2.5 Hz, 3H), 3.04 (s, 2H), 1.76 (s,3H), 1.64 (s, 2H), 1.44 (s, 2H), 1.18 (d, J = 1.5 Hz, 3H), 0.94-0.85 (m,6H). 290 402.60 2.71 291 537.50 2.20 292 460.50 1.76 293 460.50 1.46 294474.30 2.38 295 426.00 2.12 296 511.00 1.73 297 476.30 5.18 1H NMR (400MHz, DMSO) d 8.00 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.73(d, J = 8.2 Hz, 2H), 7.35 (d, J = 4.0 Hz, 1H), 7.31 (d, J = 4.2 Hz, 2H),7.27-7.20 (m, J = 8.9, 4.5 Hz, 1H), 6.47 (d, J = 4.0 Hz, 1H), 4.46 (d, J= 12.8 Hz, 1H), 3.59-3.38 (m, 3H), 3.23 (s br, 1H), 2.07 (sbr, 3H), 1.90(d, J = 12.6 Hz, 1H), 1.17 (d, J = 6.8 Hz, 6H). 298 463.20 2.08 299424.30 1.79 300 507.00 1.96 301 396.25 1.68 302 444.17 2.03 303 481.501.89 304 422.15 2.19 305 467.50 2.29 306 443.70 1.74 1H NMR (400 MHz,DMSO) d 7.85 (d, J = 1.8 Hz, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.45 (s,1H), 7.37-7.25 (m, 2H), 7.14-7.05 (m, 2H), 4.90-4.81 (m, 1H), 4.40-4.22(m, 1H), 4.10 (s, 3H), 3.63-3.42 (m, 2H), 3.30-3.18 (m, 1H), 2.07-1.81(m, 4H), 1.34 (d, J = 6.0 Hz, 6H). 307 462.20 1.74 308 442.70 1.78 309428.50 1.75 310 458.00 1.77 1H NMR (400 MHz, CDCl3) d 8.13 (d, J = 8.3Hz, 1H), 7.26-7.12 (m, 4H), 7.03 (d, J = 4.0 Hz, 1H), 6.96 (d, J = 2.4Hz, 1H), 6.81 (dd, J = 8.4, 2.4 Hz, 1H), 6.12 (d, J = 3.9 Hz, 1H),4.75-4.47 (m, 4H), 3.90-3.50 (m, 3H), 3.33 (s, 1H), 2.21 (d, J = 9.7 Hz,1H), 2.12-1.99 (m, 2H), 1.86 (s, 1H), 1.35 (d, J = 6.0 Hz, 6H). 311507.30 1.67 312 485.20 2.22 313 462.20 1.62 1H NMR (400 MHz, DMSO) d7.74 (d, J = 7.6 Hz, 1H), 7.47 (s, 1H), 7.29 (t, J = 7.7 Hz, 1H),7.16-6.99 (m, 4H), 6.95 (dd, J = 8.1, 1.5 Hz, 1H), 4.47-4.17 (m, 1H),4.10 (s, 3H), 3.77 (s, 3H), 3.72-3.33 (m, 3H), 2.10-1.81 (m, 4H), 1.29(s, 9H). 314 417.50 2.26 315 431.70 2.32 316 434.50 1.29 317 413.27 2.35318 446.00 2.03 1H NMR (400 MHz, CDCl3) d 8.14 (d, J = 7.7 Hz, 1H), 7.36(t, J = 8.3 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.20-7.11 (m, 2H), 7.04(d, J = 4.0 Hz, 1H), 6.74 (dd, J = 8.6, 2.0 Hz, 1H), 6.60 (dd, J = 11.9,2.1 Hz, 1H), 6.12 (d, J = 4.0 Hz, 1H), 4.71 (d, J = 13.0 Hz, 1H), 4.56(dt, J = 12.1, 6.1 Hz, 1H), 3.59 (d, J = 6.8 Hz, 2H), 3.31 (t, J = 12.6Hz, 1H), 2.29-1.82 (m, 5H), 1.36 (d, J = 6.0 Hz, 6H). 319 453.40 2.63320 442.20 2.41 321 458.50 1.87 1H NMR (400 MHz, CDCl3) d 7.51, 7.49,7.47, 7.45, 7.43, 7.42, 7.38, 7.36, 7.34, 7.32, 7.30, 7.28, 7.26, 7.26,7.24, 7.22, 7.13, 7.11, 7.07, 7.05, 7.04, 6.99, 5.30, 4.67, 4.50, 4.48,4.46, 4.44, 3.62, 3.58, 3.55, 3.52, 3.37, 3.33, 3.29, 2.23, 2.20, 2.03,1.94, 1.90, 1.74, 1.57, 1.54, 1.53, 1.20. 322 411.10 1.47 323 427.701.24 1H NMR (400 MHz, DMSO) d 8.59 (bs, 3H), 8.00 (d, J = 7.9 Hz, 1H),7.63 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.36-7.29 (m, 3H),7.29-7.16 (m, 1H), 6.48 (d, J = 4.1 Hz, 1H), 4.51-4.38 (m, 1H),3.70-3.47 (m, 2H), 3.20 (s, 1H), 2.18-1.88 (m, 4H), 1.65 (s, 6H). 324431.02 2.80 325 432.50 1.13 326 447.50 2.08 327 465.50 1.81 1H NMR (400MHz, CDCl3) d 7.97-7.91 (m, 2H), 7.64-7.57 (m, 2H), 7.36 (d, J = 7.3 Hz,1H), 7.16-7.13 (m, 1H), 7.11-7.01 (m, 3H), 6.36-6.29 (m, 1H), 6.07-5.99(m, 1H), 4.71-4.59 (m, 1H), 3.70-3.27 (m, 3H), 2.33-1.75 (m, 4H), 1.36(s, 9H). 328 442.50 1.86 1H NMR (400 MHz, CDCl3) d 7.52, 7.49, 7.47,7.26, 7.21, 7.15, 7.13, 7.10, 7.08, 7.08, 7.07, 7.06, 7.04, 7.04, 7.02,7.02, 4.66, 4.13, 3.99, 3.99, 3.81, 3.61, 3.58, 3.55, 3.48, 3.46, 3.44,3.39, 3.36, 3.33, 3.30, 3.27, 2.21, 2.17, 2.01, 1.97, 1.94, 1.93, 1.90,1.89, 1.75, 1.73, 1.69, 1.62, 1.57, 1.53. 329 496.26 1.95 330 506.302.17 331 443.12 2.43 332 407.50 5.96 333 500.30 1.59 334 472.30 1.74 1HNMR (400 MHz, CDCl3) d 8.12 (d, J = 7.3 Hz, 1H), 7.37 (d, J = 8.5 Hz,2H), 7.24-7.18 (m, 1H), 7.18-7.09 (m, 2H), 7.02 (d, J = 3.8 Hz, 1H),6.86 (d, J = 8.5 Hz, 2H), 6.11 (d, J = 3.8 Hz, 1H), 4.64 (s, 1H),3.91-3.26 (m, 4H), 2.26-1.77 (m, 6H), 1.61 (s, 6H). 335 477.22 2.26 336496.20 1.42 1H NMR (400 MHz, DMSO) d.7.77-7.69 (m, 1H), 7.63-7.40 (m,4H), 7.28 (t, J = 7.7 Hz, 1H), 7.18-7.02 (m, 2H), 4.41 (d, J = 12.1 Hz,1H), 4.15-4.05 (m, 3H), 3.98-3.88 (m, 3H), 3.60-3.49 (m, 1H), 3.49-3.35(m, 1H), 3.30-3.11 (m, 2H), 2.10-1.76 (m, 4H), 1.22-1.14 (m, 6H). 337480.30 2.10 338 442.70 2.13 339 433.50 2.40 340 444.50 1.70 341 479.302.16 342 459.20 2.68 343 404.07 1.95 344 495.20 1.49 345 440.12 2.32 346418.27 1.54 347 471.20 2.52 1H NMR (400 MHz, CDCl3) d 7.67 (d, J = 8.1Hz, 1H), 7.21-7.05 (m, 4H), 6.97-6.89 (m, 2H), 6.81 (d, J = 3.9 Hz, 1H),6.06 (d, J = 3.9 Hz, 1H), 4.96-4.23 (m, 1H), 3.84 (s, 3H), 3.64-3.14 (m,3H), 2.64 (q, J = 7.5 Hz, 2H), 2.25-1.75 (m, 4H), 1.17 (t, J = 7.5 Hz,3H). 348 509.70 1.92 349 391.20 3.01 350 430.40 2.91 351 387.20 2.50 352433.30 2.36 1H NMR (400 MHz, DMSO) d 7.66 (d, J = 7.7 Hz, 1H), 7.51-7.47(m, 1H), 7.18-6.95 (m, 6H), 6.28 (t, J = 3.1 Hz, 1H), 6.17 (d, J = 3.4Hz, 1H), 4.58-4.04 (m, 1H), 3.94 (t, J = 6.5 Hz, 2H), 3.78 (s, 3H),3.59-3.13 (m, 3H), 2.03-1.86 (m, 4H), 1.73 (sextet, J = 6.8 Hz, 2H),0.97 (t, J = 7.4 Hz, 3H). 353 426.20 2.97 354 422.19 2.00 355 450.301.53 1H NMR (400 MHz, DMSO) ? 7.73 (d, J = 7.4 Hz, 1H), 7.46 (s, 1H),7.28 (t, J = 7.2 Hz, 1H), 7.19-6.80 (m, 4H), 4.39 (s, 1H), 4.10 (s, 3H),3.79 (d, J = 22.0 Hz, 9H), 3.42 (s, 1H), 3.27-3.14 (m, 1H), 1.92 (d, J =49.8 Hz, 4H). 356 447.13 2.84 357 479.30 1.54 1H NMR (400 MHz, DMSO) ?7.96 (d, J = 7.9 Hz, 1H), 7.58-7.50 (m, 3H), 7.37 (d, J = 4.1 Hz, 1H),7.25-7.13 (m, J = 9.4, 8.0, 1.6 Hz, 2H), 7.08-6.99 (m, 1H), 6.38 (d, J =4.0 Hz, 1H), 4.45 (d, J = 12.4 Hz, 1H), 3.47 (dd, J = 22.7, 14.5 Hz,2H), 3.25 (s, 3H), 3.23-3.10 (m, 1H), 2.68 (s, 3H), 2.49 (s, 3H),2.14-2.00 (m, 1H), 1.94 (s br, 2H), 1.80 (d, J = 13.9 Hz, 1H). 358420.17 1.59 359 431.00 2.31 360 453.30 1.75 361 428.10 2.54 362 476.202.95 363 490.30 1.86 1H NMR (400 MHz, CDCl3) d 8.13 (d, J = 7.3 Hz, 1H),8.03 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 7.8 Hz,1H), 7.15 (t, J = 7.2 Hz, 2H), 7.03 (d, J = 4.0 Hz, 1H), 6.11 (d, J =3.9 Hz, 1H), 4.73-4.64 (m, 1H), 3.62-3.51 (m, 2H), 3.40-3.30 (m, 1H),3.30-3.20 (m, 1H), 2.72 (s, 3H), 2.29-2.17 (m, 1H), 2.12-1.97 (m, 2H),1.87-1.75 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H). 364 458.50 1.58 365 448.201.74 366 509.50 1.86 367 447.50 2.22 1H NMR (400 MHz, CDCl3) d 7.72 (d,J = 10.5 Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H),7.33-7.25 (m, 3H), 7.13 (d, J = 1.9 Hz, 2H), 7.04 (dd, J = 8.5, 2.1 Hz,1H), 6.36 (t, J = 3.1 Hz, 1H), 6.11-6.04 (m, 1H), 4.67 (s, 1H), 3.61(br. s, 2H), 3.38 (br. s, 1H), 2.22 (br. s, 1H), 2.08 (br. s, 2H), 1.88(br. s, 1H), 1.60 (s, 5H). 368 490.30 2.07 369 430.70 1.81 370 466.103.39 371 363.50 1.89 372 460.30 2.18 373 374 481.50 1.94 375 472.50 1.901H NMR (400 MHz, CDCl3) d 7.98 (d, J = 8.2 Hz, 1H), 7.41 (s, 1H), 7.37(d, J = 8.4 Hz, 1H), 6.99 (d, J = 4.0 Hz, 1H), 6.96 (s, 1H), 6.93 (d, J= 8.7 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.07 (d, J = 4.0 Hz, 1H), 4.67(s, 2H), 4.66-4.60 (m, 1H), 4.06-3.26 (m, 3H), 2.36 (s, 3H), 2.19-1.82(m, 5H), 1.37 (d, J = 6.0 Hz, 6H). 376 471.50 3.29 377 405.10 2.51 378379 445.50 1.50 380 467.31 2.27 381 426.12 1.68 1H NMR (400 MHz, CDCl3)? 7.57 (dd, J = 7.7, 1.4 Hz, 1H), 7.45-7.34 (m, 2H), 7.33-7.17 (m, 4H),7.14-7.00 (m, 2H), 6.58 (dd, J = 77.9, 70.8 Hz, 1H), 4.66 (t, J = 13.1Hz, 1H), 4.16 (s, 3H), 3.68-3.51 (m, 1H), 3.43-3.27 (m, 2H), 2.26-2.15(m, 1H), 2.13-1.99 (m, 1H), 1.99-1.88 (m, 1H), 1.82-1.66 (m, 1H). 382462.50 1.85 383 408.50 1.62 384 391.30 1.38 385 427.25 2.45 386 429.202.00 387 486.20 2.05 388 444.10 1.65 390 443.12 2.21 391 532.20 1.71 392502.00 2.20 1H NMR (400 MHz, CDCl3) d 8.06 (t, J = 10.1 Hz, 1H), 7.70(s, 1H), 7.64 (dd, J = 8.6, 1.6 Hz, 1H), 7.17 (d, J = 2.2 Hz, 1H), 7.10(dd, J = 8.7, 2.2 Hz, 1H), 7.03 (dd, J = 10.4, 6.3 Hz, 2H), 6.13 (d, J =4.0 Hz, 1H), 4.61 (s, 1H), 3.96 (d, J = 20.2 Hz, 3H), 3.89-3.06 (m, 3H),2.16-1.81 (m, 4H). 393 434.50 1.91 394 451.30 7.62 395 417.50 2.30 396406.20 1.19 1H NMR (400 MHz, DMSO) d 9.44 (s, 1H), 7.73 (d, J = 7.7 Hz,1H), 7.47 (s, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.16-7.05 (m, 2H), 7.00 (s,1H), 6.91 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.10 (s, 3H),4.18-4.02 (m, 1H), 3.79 (s, 3H), 3.54-3.25 (m, 3H), 2.06-1.78 (m, 4H).397 407.24 2.16 398 490.50 1.47 399 447.50 7.60 H NMR (400.0 MHz, DMSO)d 7.68-7.65 (m, 1H), 7.50-7.49 (m, 1H), 7.40 (d, J = 7.9 Hz, 1H),7.17-6.98 (m, 5H), 6.29-6.28 (m, 1H), 6.18-6.17 (m, 1H), 4.49-4.34 (m,1H), 3.83 (s, 3H), 3.80-3.41 (m, 3H), 3.13 (s, 3H), 2.11-1.81 (m, 4H)and 1.50 (s, 6H) ppm. 400 465.21 2.23 401 420.00 1.89 1H NMR (400 MHz,CDCl3) d 8.14 (d, J = 8.1 Hz, 1H), 7.76-7.67 (m, 1H), 7.58-7.49 (m, 2H),7.38-7.32 (m, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.20-7.13 (m, 2H), 7.04 (d,J = 3.9 Hz, 1H), 6.12 (s, 1H), 4.72 (s, 1H), 3.37 (dd, J = 46.1, 33.5Hz, 3H), 2.20 (s, 1H), 1.96 (dd, J = 56.3, 18.6 Hz, 3H). 402 453.28 2.25403 490.40 3.05 404 543.00 1.75 405 376.50 1.43 406 444.40 1.51 1H NMR(400 MHz, CDCl3) d 8.12 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H),7.44 (d, J = 8.2 Hz, 2H), 7.25-7.19 (m, 1H), 7.17-7.11 (m, 2H), 7.02 (d,J = 3.9 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H), 4.66 (s, 1H), 3.78 (d, J =11.1 Hz, 1H), 3.65 (d, J = 11.1 Hz, 1H), 3.49 (s, 1H), 3.33 (s, 1H),2.10 (s, 1H), 1.84 (s, 4H), 1.53 (s, 3H). 407 497.50 2.03 408 486.351.70 1H NMR (400 MHz, CDCl3) d 8.12 (d, J = 8.5 Hz, 1H), 7.25-7.17 (m,3H), 7.18-7.10 (m, 2H), 7.02 (d, J = 4.0 Hz, 1H), 6.70 (d, J = 9.0 Hz,1H), 6.10 (d, J = 4.0 Hz, 1H), 4.66 (s, 1H), 3.74 (dd, J = 103.4, 60.3Hz, 4H), 2.23 (s, 3H), 2.02 (dd, J = 92.2, 67.9 Hz, 5H), 1.61 (s, 6H).409 412.50 1.69 410 446.50 6.31 1H NMR (400 MHz, CDCl3) d 7.50 (d, J =7.8 Hz, 1H), 7.31 (s, 1H), 7.29-7.22 (m, 3H), 7.11-7.02 (m, 2H), 6.82(d, J = 8.1 Hz, 1H), 4.56 (sept, J = 6.1 Hz, 1H), 4.50 (s, 1H), 4.48 (q,J = 7.3 Hz, 2H), 3.84 (s, 1H), 3.48 (s, 2H), 2.21 (s, 3H), 2.10 (s, 1H),1.90 (s, 2H), 1.75 (s, 1H), 1.55 (t, J = 7.3 Hz, 3H), 1.35 (d, J = 6.0Hz, 6H). 411 518.30 1.55 412 432.30 1.76 413 534.50 2.07 414 433.70 1.91415 417.13 2.89 416 460.00 2.08 417 481.20 3.03 418 432.50 1.29 1H NMR(400 MHz, CDCl3) d 7.64 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 7.7 Hz, 1H),7.44 (d, J = 8.2 Hz, 2H), 7.29-7.23 (m, 3H), 7.10-7.02 (m, 2H), 4.93 (d,J = 7.0 Hz, 2H), 4.83 (d, J = 7.0 Hz, 2H), 4.60 (bs, 1H), 4.15 (s, 3H),3.80-3.21 (m, 4H), 2.29-1.44 (m, 4H). 419 426.50 7.85 H NMR (400.0 MHz,DMSO) d 7.93 (d, J = 1.7 Hz, 1H), 7.73 (m, 1H), 7.68-7.63 (m, 2H), 7.50(m, 1H), 7.17-7.05 (m, 3H), 6.29 (t, J = 3.2 Hz, 1H), 6.16 (dd, J = 1.3,3.4 Hz, 1H), 4.48-4.34 (m, 1H), 3.59-3.41 (m, 2H), 3.23 (m, 1H),2.10-1.85 (m, 4H) and 1.48 (s, 9H) ppm. 420 464.20 2.38 421 411.23 2.18422 430.70 1.77 423 480.30 2.31 424 489.50 2.04 1H NMR (400 MHz, CDCl3)d 7.71-7.59 (m, 2H), 7.23-7.06 (m, 5H), 6.81 (d, J = 3.9 Hz, 1H), 6.06(d, J = 3.9 Hz, 1H), 4.63 (s, 1H), 3.68 (s, 1H), 3.56 (s, 1H), 3.31 (s,1H), 2.16 (s, 1H), 2.03-1.90 (m, 1H), 1.82 (d, J = 21.3 Hz, 1H), 1.64(s, 6H). 425 448.50 1.32 426 490.30 1.83 1H NMR (400 MHz, CDCl3) d 8.13(d, J = 7.4 Hz, 1H), 7.76 (d, J = 9.1 Hz, 2H), 7.43-7.36 (m, 1H), 7.22(d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.0 Hz, 2H), 7.03 (d, J = 3.9 Hz, 1H),6.14-6.06 (m, 1H), 4.76 (d, J = 13.5 Hz, 1H), 3.52 (t, J = 12.1 Hz, 1H),3.41-3.24 (m, 2H), 3.24-3.16 (m, 1H), 2.44 (d, J = 13.7 Hz, 3H), 2.25(d, J = 15.6 Hz, 1H), 2.10-1.95 (m, 3H), 1.84-1.73 (m, 1H), 1.31 (d, J =6.9 Hz, 6H). 427 476.30 2.12 428 489.25 1.95 429 446.20 2.49 430 418.301.90 431 506.50 1.49 1H NMR (400 MHz, DMSO) d 7.93 (dd, J = 8.2, 6.5 Hz,3H), 7.73 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 4.0 Hz, 1H), 7.25 (s, 1H),7.15 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 4.1 Hz, 1H), 5.39-5.30 (m, 1H),4.51 (s, 2H), 3.81-3.64 (m, 1H), 3.54-3.42 (m, 2H), 3.41-3.37 (m, 1H),2.20-2.12 (m, 1H), 2.13-2.03 (m, 1H), 2.01 (t, J = 5.9 Hz, 1H), 1.57(dd, J = 12.5, 6.2 Hz, 1H), 1.17 (d, J = 6.8 Hz, 6H). 432 411.23 2.18433 404.20 1.75 434 443.20 2.12 435 466.50 1.72 436 490.30 1.90 1H NMR(400 MHz, CDCl3) d 8.13 (d, J = 7.5 Hz, 1H), 7.98 (d, J = 8.3 Hz, 2H),7.62 (d, J = 8.3 Hz, 2H), 7.26-7.21 (m, 1H), 7.15 (t, J = 7.2 Hz, 2H),7.03 (d, J = 4.0 Hz, 1H), 6.11 (d, J = 4.0 Hz, 1H), 4.69 (d, J = 11.9Hz, 1H), 3.66-3.48 (m, 2H), 3.40-3.28 (m, 1H), 3.00 (d, J = 6.5 Hz, 2H),2.30-2.16 (m, 2H), 2.12-1.98 (m, 2H), 1.88-1.75 (m, 1H), 1.08 (s, 3H),1.07 (s, 3H). 437 475.30 1.76 438 444.20 5.86 1H NMR (400 MHz, CDCl3) d8.24 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 8.2 Hz,1H), 7.31 (dd, J = 8.7, 2.9 Hz, 1H), 7.21-7.05 (m, 3H), 6.80 (d, J = 3.9Hz, 1H), 6.08 (d, J = 3.9 Hz, 1H), 4.65 (d, J = 12.3 Hz, 1H), 4.10 (d, J= 12.5 Hz, 1H), 3.90 (s, 3H), 3.61 (t, J = 13.0 Hz, 1H), 3.33 (t, J =12.4 Hz, 1H), 2.23-1.98 (m, J = 17.2 Hz, 4H). 439 412.30 1.35 440 490.301.84 1H NMR (400 MHz, CDCl3) d 8.00 (d, J = 8.1 Hz, 1H), 7.95 (d, J =8.3 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 4.0 Hz, 1H), 6.94(d, J = 10.0 Hz, 2H), 6.09 (d, J = 4.0 Hz, 1H), 4.69 (d, J = 11.7 Hz,1H), 3.65-3.47 (m, 2H), 3.34 (t, J = 12.1 Hz, 1H), 3.21 (dt, J = 13.7,6.9 Hz, 1H), 2.36 (s, 3H), 2.29-2.16 (m, 1H), 2.11-1.95 (m, 2H),1.90-1.71 (m, 1H), 1.31 (d, J = 6.9 Hz, 6H). 441 457.27 2.43 442 430.402.95 443 417.50 1.86 444 400.00 1.35 445 485.50 1.75 1H NMR (400 MHz,CDCl3) d 8.59, 8.57, 7.52, 7.31, 7.26, 7.23, 7.22, 7.21, 7.16, 7.14,7.13, 7.11, 7.09, 7.01, 6.99, 6.97, 6.93, 6.15, 4.74, 4.70, 4.14, 4.12,4.10, 4.08, 3.51, 3.29, 3.08, 2.21, 2.17, 2.08, 2.07, 2.05, 2.04, 2.01,1.61, 1.56, 1.51, 1.47, 1.45, 1.44. 446 458.50 1.78 447 432.50 1.46 448431.20 2.24 1H NMR (400 MHz, CDCl3) d 7.56 (d, J = 7.7 Hz, 1H),7.45-7.37 (m, 3H), 7.46-7.22 (m, 2H), 7.30-7.21 (m, 1H), 7.13-7.00 (m,2H), 4.52 (d, J = 13.5 Hz, 1H), 4.19 (s, 3H), 3.74-3.51 (m, 2H), 3.31(t, J = 11.9 Hz, 1H), 3.09 (s, 3H), 2.94 (s, 3H), 2.24-2.02 (m, J = 13.9Hz, 2H), 2.02-1.76 (m, 2H). 449 463.50 1.98 450 414.25 2.26 451 463.302.27 1H NMR (400 MHz, CDCl3) d 7.49 (t, J = 7.7 Hz, 1H), 7.40 (d, J =7.6 Hz, 1H), 7.29 (dd, J = 11.7, 6.5 Hz, 4H), 7.12 (d, J = 1.8 Hz, 2H),7.04 (dd, J = 8.5, 2.1 Hz, 1H), 6.36 (t, J = 3.2 Hz, 1H), 6.07 (d, J =3.3 Hz, 1H), 4.65 (br s, 1H), 3.62 (br s, 2H), 3.36 (br s, 1H), 2.21 (brs, 1H), 2.08 (br s, 2H), 1.87 (br s, 1H), 1.62 (s, 2H). 452 444.10 1.79453 418.10 2.33 454 460.50 1.44 455 472.00 1.63 1H NMR (400 MHz, CDCl3)d 8.63 (s, 1H), 7.83 (dd, J = 8.1, 1.6 Hz, 1H), 7.70 (d, J = 8.1 Hz,1H), 7.49 (d, J = 8.1 Hz, 1H), 7.17 (tt, J = 15.4, 7.6 Hz, 3H), 6.84 (d,J = 3.9 Hz, 1H), 6.08 (d, J = 3.9 Hz, 1H), 4.65 (d, J = 20.8 Hz, 1H),3.68 (s, 2H), 3.37 (s, 1H), 2.82 (s, 1H), 2.30-1.99 (m, 3H), 1.90 (s,1H), 1.58 (s, 6H). 456 505.30 1.96 1H NMR (400 MHz, DMSO) d 7.96 (d, J =8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H),7.34-7.17 (m, 3H), 7.03 (d, J = 3.9 Hz, 1H), 6.40 (d, J = 3.9 Hz, 1H),4.51-4.37 (m, 1H), 3.62-3.11 (m, 3H), 3.35 (q, J = 7.3 Hz, 2H),2.19-1.75 (m, 4H), 1.12 (t, J = 7.3 Hz, 3H). 457 472.25 1.52 458 459.502.01 459 429.50 2.30 460 429.30 1.57 461 394.10 1.76 462 458.50 1.68 1HNMR (400 MHz, CDCl3) d 8.12 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.4 Hz,1H), 7.25-7.18 (m, 2H), 7.18-7.09 (m, 2H), 7.01 (d, J = 4.0 Hz, 1H),6.63 (d, J = 8.5 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H), 5.70-5.30 (m, 2H),4.63 (s, 2H), 3.68-3.23 (m, 2H), 2.27 (s, 3H), 2.21-2.02 (m, 2H),1.99-1.74 (m, 2H). 463 429.30 1.53 464 418.30 2.38 465 404.30 1.67 466449.10 1.41 467 418.30 1.95 468 462.30 2.33 469 508.30 1.58 470 406.202.80 471 461.22 2.52 472 524.30 2.18 473 432.70 1.60 474 435.50 1.63 475427.50 2.12 1H NMR (400 MHz, CDCl3) d 7.26 (d, J = 8.4 Hz, 1H),7.13-7.07 (m, 2H), 7.05-6.96 (m, 2H), 6.94-6.85 (m, 2H), 6.33 (t, J =3.2 Hz, 1H), 6.08-5.98 (m, 1H), 4.69 (d, J = 13.1 Hz, 1H), 3.80 (s, 3H),3.63-3.44 (m, 2H), 3.33 (t, J = 12.8 Hz, 1H), 2.19 (d, J = 13.8 Hz, 1H),2.09-1.96 (m, 2H), 1.60 (s, 1H). 476 408.40 2.86 477 443.10 2.62 478423.50 2.17 1H NMR (400 MHz, CDCl3) d 7.30 (dt, J = 8.4, 6.8 Hz, 3H),7.12 (d, J = 2.0 Hz, 2H), 7.01 (ddd, J = 20.7, 10.7, 4.8 Hz, 4H), 6.36(t, J = 3.1 Hz, 1H), 6.06 (d, J = 2.9 Hz, 1H), 4.65 (br s, 1H), 4.07 (q,J = 7.0 Hz, 2H), 3.71 (br s, 1H), 3.55 (br s, 1H), 3.33 (br s, 1H), 2.19(br s, 1H), 2.05 (br s, 2H), 1.86 (br s, 1H), 1.62 (br s, 3H), 1.44 (t,J = 7.0 Hz, 3H). 479 486.00 2.03 1H NMR (400 MHz, CDCl3) d 8.10 (dd, J =9.0, 5.2 Hz, 1H), 7.70 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.03 (dd, J =10.3, 6.1 Hz, 2H), 6.94-6.82 (m, 2H), 6.11 (d, J = 4.0 Hz, 1H), 4.61 (s,1H), 3.95 (s, 3H), 3.49 (s, 3H), 2.03 (d, J = 66.9 Hz, 4H). 480 456.501.82 481 437.00 2.05 1H NMR (400 MHz, CDCl3) d 8.16-7.94 (m, 1H), 7.60(d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.17-7.10 (m, 1H),7.10-7.00 (m, 2H), 6.93 (d, J = 4.0 Hz, 1H), 6.02 (d, J = 4.0 Hz, 1H),4.60 (d, J = 10.9 Hz, 1H), 3.51 (s, 2H), 3.41-3.08 (m, 1H), 2.13 (d, J =11.5 Hz, 1H), 1.95 (s, 3H), 1.78 (d, J = 8.8 Hz, 1H). 482 481.50 2.23483 533.50 2.10 1H NMR (400 MHz, DMSO) d 7.89 (d, J = 8.0 Hz, 2H), 7.73(d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.35-7.25 (m, 2H),7.25-7.16 (m, 1H), 7.03 (d, J = 3.9 Hz, 1H), 6.40 (d, J = 3.9 Hz, 1H),4.53-4.37 (m, 1H), 3.57-3.14 (m, 3H), 2.17-1.78 (m, 4H), 1.26 (s, 9H).484 477.22 2.20 485 432.50 1.96 1H NMR (400 MHz, CDCl3) d 8.15, 8.13,7.54, 7.28, 7.26, 7.24, 7.22, 7.17, 7.16, 7.14, 7.12, 7.04, 7.03, 7.02,7.00, 6.97, 6.95, 6.12, 4.76, 4.73, 4.16, 4.14, 4.13, 4.11, 3.55, 3.31,2.24, 2.20, 2.07, 2.05, 2.03, 2.02, 2.00, 1.99, 1.63, 1.58, 1.54, 1.49,1.48, 1.46. 486 436.50 1.46 487 443.70 1.83 488 497.50 1.78 489 423.306.50 490 456.00 2.20 1H NMR (400 MHz, CDCl3) d 7.28-7.22 (m, 2H), 7.18(t, J = 7.9 Hz, 1H), 7.09 (d, J = 3.7 Hz, 1H), 7.03 (dd, J = 13.1, 7.9Hz, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.18 (d, J = 4.0 Hz, 1H), 4.57 (dt, J= 12.1, 6.0 Hz, 2H), 3.43 (d, J = 6.4 Hz, 3H), 2.70 (s, 3H), 2.22 (d, J= 3.5 Hz, 3H), 2.05 (t, J = 15.1 Hz, 5H), 1.36 (d, J = 6.0 Hz, 7H). 491374.20 2.04 492 467.20 2.50 1H NMR (400 MHz, DMSO) d 7.71 (d, J = 8.6Hz, 1H), 7.52 (d, J = 1.5 Hz, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.14 (dd, J= 8.6, 2.2 Hz, 1H), 7.07-6.95 (m, 3H), 6.30 (t, J = 3.1 Hz, 1H), 6.20(d, J = 3.3 Hz, 1H), 4.63-4.07 (m, 1H), 3.94 (t, J = 6.5 Hz, 2H), 3.79(s, 3H), 3.59-3.14 (m, 3H), 2.08-1.86 (m, 4H), 1.73 (sextet, J = 7.0 Hz,2H), 0.97 (t, J = 7.4 Hz, 3H). 493 451.23 2.25 494 453.30 1.40 1H NMR(400 MHz, DMSO) d 7.84 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 7.7 Hz, 1H),7.69 (d, J = 8.1 Hz, 2H), 7.48 (s, 1H), 7.46 (s, 1H), 7.33-7.25 (m, 1H),7.15-7.04 (m, 2H), 4.45-4.34 (m, 1H), 4.10 (s, 3H), 3.61-3.21 (m, 3H),2.44 (s, 3H), 2.08-1.82 (m, 4H). 495 465.50 4.00 496 420.30 3.60 1H NMR(400 MHz, DMSO) d 7.73 (dd, J = 7.7, 1.1 Hz, 1H), 7.47 (s, 1H), 7.41 (d,J = 8.6 Hz, 2H), 7.33-7.25 (m, 1H), 7.16-7.04 (m, 2H), 6.99 (d, J = 8.7Hz, 2H), 4.88 (t, J = 5.4 Hz, 1H), 4.49-4.16 (m, 1H), 4.10 (s, 3H), 4.03(t, J = 4.9 Hz, 2H), 3.77-3.67 (m, 2H), 3.66-3.18 (m, 3H), 2.02-1.83 (m,4H). 497 481.10 2.03 1H NMR (400 MHz, DMSO) d 7.71 (d, J = 8.6 Hz, 1H),7.52 (dd, J = 2.8, 1.3 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.29 (d, J =2.3 Hz, 1H), 7.14 (dd, J = 8.6, 2.3 Hz, 1H), 7.05 (d, J = 1.3 Hz, 1H),7.01 (dd, J = 7.8, 1.3 Hz, 1H), 6.30 (t, J = 3.2 Hz, 1H), 6.20 (dd, J =3.5, 1.2 Hz, 1H), 4.55-4.25 (m, 1H), 3.83 (s, 3H), 3.74-3.39 (m, 3H),3.13 (s, 3H), 2.06-1.86 (m, 4H), 1.50 (s, 6H). 498 505.30 2.56 1H NMR(400 MHz, CDCl3) d 7.59 (d, J = 8.8 Hz, 1H), 7.18-7.10 (m, 2H), 7.07(dd, J = 8.8, 2.4 Hz, 1H), 6.96-6.87 (m, 2H), 6.81 (d, J = 3.6 Hz, 1H),6.07 (d, J = 3.8 Hz, 1H), 4.92-4.24 (m, 1H), 3.85 (s, 3H), 3.66-3.03 (m,3H), 2.64 (q, J = 7.5 Hz, 2H), 2.31-1.75 (m, 4H), 1.18 (t, J = 7.5 Hz,3H). 499 404.27 1.44 500 418.40 3.93 501 481.50 4.04 502 424.30 1.63 1HNMR (400 MHz, CDCl3) d 8.24, 7.04, 7.02, 6.84, 6.82, 6.69, 6.65, 6.64,6.61, 6.56, 6.46, 6.45, 6.38, 6.38, 6.36, 6.36, 6.25, 6.22, 5.90, 5.70,5.69, 5.68, 5.51, 5.49, 5.44, 5.43, 5.30, 5.28, 5.22, 4.02, 3.99, 3.36,3.10, 2.97, 2.92, 2.86, 2.84, 2.74, 2.69, 2.66, 2.63, 1.99, 1.92, 1.86,1.81, 1.76, 1.71, 1.60, 1.54, 1.50, 1.45, 1.44, 1.41, 1.38, 1.26, 1.21,0.79, −1.64. 503 483.97 3.83 504 516.00 1.88 1H NMR (400 MHz, CDCl3) d8.38 (d, J = 8.1 Hz, 1H), 8.19-8.09 (m, 1H), 7.97 (s, 1H), 7.82 (d, J =8.1 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.19-7.11 (m, 2H), 7.03 (d, J =4.0 Hz, 1H), 6.13 (d, J = 4.0 Hz, 1H), 4.69 (d, J = 11.7 Hz, 1H),3.86-3.28 (m, 3H), 3.20 (s, 3H), 2.11 (d, J = 50.6 Hz, 16H), 1.99-1.79(m, 2H). 505 503.95 4.25 506 418.50 1.47 1H NMR (400 MHz, CDCl3) d7.64-7.50 (m, 3H), 7.44 (t, J = 12.1 Hz, 2H), 7.33-7.21 (m, 2H), 7.06(dd, J = 15.7, 8.0 Hz, 2H), 4.60 (m, 1H), 4.17 (s, 3H), 3.82-3.49 (m,2H), 3.43 (m, 1H), 2.33-1.69 (m, 5H), 1.59 (s, 6H). 507 463.00 1.34 508469.50 1.86 1H NMR (400 MHz, CDCl3) d 7.96 (d, J = 8.3 Hz, 2H), 7.63 (d,J = 8.3 Hz, 2H), 7.29 (d, J = 22.7 Hz, 1H), 7.11-7.01 (m, 4H), 6.92 (t,J = 3.8 Hz, 1H), 6.12 (d, J = 3.3 Hz, 1H), 4.67 (d, J = 12.5 Hz, 1H),3.69-3.46 (m, 2H), 3.40-3.27 (m, 1H), 3.21 (dt, J = 13.7, 6.8 Hz, 2H),2.15 (d, J = 56.6 Hz, 4H), 1.54 (s, 1H), 1.31 (d, J = 6.9 Hz, 8H). 5091H NMR (400 MHz, DMSO) d 8.00 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 7.9 Hz,1H), 7.58-7.50 (m, J = 8.6 Hz, 2H), 7.35 (d, J = 4.0 Hz, 1H), 7.34-7.28(m, J = 4.1 Hz, 2H), 7.28-7.20 (m, 1H), 6.48 (d, J = 4.0 Hz, 1H), 4.45(d, J = 12.5 Hz, 1H), 3.59-3.42 (m, J = 20.8 Hz, 2H), 3.25 (s, 3H), 3.19(br d, 1H), 2.68 (s, 3H), 2.16-2.00 (m, J = 22.8 Hz, 3H), 1.90 (d, J =13.1 Hz, 1H). 510 408.26 1.60 511 428.50 2.07 512 449.00 3.32 513 457.501.82 1H NMR (400 MHz, CDCl3) d 8.04 (d, J = 8.4 Hz, 2H), 7.76 (d, J =7.3 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 4.1 Hz, 2H), 7.13(d, J = 1.9 Hz, 2H), 7.04 (dd, J = 8.5, 1.8 Hz, 1H), 6.36 (t, J = 3.1Hz, 1H), 6.07 (d, J = 3.4 Hz, 1H), 4.67 (br s, 1H), 3.59 (br s, 2H),3.38 (br s, 1H), 3.10 (s, 3H), 2.22 (br s, 1H), 2.06 (br s, 2H), 1.89(br s, 1H), 1.62 (s, 4H). 514 488.00 1.79 1H NMR (400 MHz, CDCl3) d 7.41(d, J = 7.9 Hz, 1H), 7.25 (d, J = 8.1 Hz, 2H), 7.19-7.02 (m, 3H), 6.83(d, J = 8.1 Hz, 1H), 6.26 (d, J = 3.4 Hz, 1H), 5.99 (d, J = 3.5 Hz, 1H),5.68 (s, 1H), 4.71 (d, J = 4.7 Hz, 2H), 4.57 (dt, J = 12.0, 6.1 Hz, 2H),4.00-3.30 (m, 3H), 2.23 (s, 3H), 2.20-1.75 (m, 4H), 1.36 (d, J = 6.0 Hz,6H). 515 492.20 2.44 516 414.50 1.58 1H NMR (400 MHz, DMSO) d 7.99 (d, J= 7.8 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.38-7.13 (m, 6H), 6.50 (t, J =4.4 Hz, 1H), 5.15 (t, J = 5.3 Hz, 1H), 4.52 (d, J = 5.4 Hz, 3H),3.53-3.03 (m, 4H), 2.23-1.66 (m, 6H). 517 446.14 2.39 518 478.20 2.62519 418.00 1.81 1H NMR (400 MHz, CDCl3) d 8.14 (d, J = 8.1 Hz, 1H),7.38-7.31 (m, 1H), 7.23 (dd, J = 8.7, 6.6 Hz, 1H), 7.20-7.12 (m, 2H),7.04 (d, J = 4.0 Hz, 1H), 6.82-6.71 (m, 2H), 6.11 (dd, J = 10.3, 4.0 Hz,1H), 4.79 (d, J = 13.3 Hz, 1H), 3.88 (d, J = 7.4 Hz, 3H), 3.62-3.24 (m,3H), 2.31-2.17 (m, 1H), 2.17-1.81 (m, 3H). 520 394.30 1.83 521 467.301.47 1H NMR (400 MHz, DMSO) d 7.85 (d, J = 8.1 Hz, 2H), 7.79-7.52 (m,4H), 7.46 (s, 1H), 7.33-7.25 (m, 1H), 7.15-7.04 (m, 2H), 4.46-4.32 (m,1H), 4.10 (s, 3H), 3.64-3.20 (m, 3H), 2.81 (q, J = 7.2 Hz, 2H),2.09-1.81 (m, 4H), 0.98 (t, J = 7.2 Hz, 3H). 522 476.30 1.80 1H NMR (400MHz, CDCl3) d 8.09 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.41(s, 1H), 7.40 (d, J = 7.0 Hz, 1H), 7.00 (d, J = 4.0 Hz, 1H), 6.95 (s,1H), 6.94 (d, J = 10.2 Hz, 1H), 6.09 (d, J = 4.0 Hz, 1H), 4.68 (d, J =11.8 Hz, 1H), 3.65-3.53 (m, 2H), 3.32 (t, J = 12.6 Hz, 1H), 3.09 (s,3H), 2.75 (s, 3H), 2.36 (s, 3H), 2.27-2.17 (m, 1H), 2.11-1.96 (m, 2H),1.86-1.75 (m, 1H). 523 467.50 1.43 1H NMR (400 MHz, DMSO) d 7.85 (d, J =8.0 Hz, 1H), 7.74 (s, 1H), 7.64-7.55 (m, 2H), 7.49 (s, 1H), 7.45 (d, J =8.2 Hz, 1H), 7.25-7.16 (m, 1H), 7.06-6.94 (m, 2H), 4.33 (d, J = 11.7 Hz,1H), 3.88 (s, 3H), 3.62-3.48 (m, 1H), 3.48-3.34 (m, 2H), 2.60 (s, 3H),2.46 (d, J = 4.9 Hz, 3H), 2.10-1.98 (m, 1H), 1.97-1.82 (m, 3H). 524432.50 1.18 525 432.70 1.51 526 458.28 1.76 527 463.10 1.68 528 458.501.80 1H NMR (400 MHz, CDCl3) d 7.52, 7.50, 7.33, 7.30, 7.29, 7.27, 7.24,7.22, 7.17, 7.15, 7.12, 7.08, 7.07, 7.05, 7.01, 6.84, 6.65, 6.47, 4.69,4.65, 4.51, 4.49, 4.47, 4.45, 4.00, 3.65, 3.61, 3.58, 3.56, 3.51, 3.50,3.48, 3.46, 3.40, 3.36, 3.34, 3.30, 2.23, 2.19, 2.07, 2.02, 1.98, 1.97,1.94, 1.93, 1.91, 1.76, 1.63, 1.61, 1.58, 1.55, 1.53, 1.23, 1.22, 1.20.529 465.10 2.37 530 484.50 5.64 531 501.30 2.01 1H NMR (400 MHz, DMSO) d7.57 (d, J = 8.1 Hz, 1H), 7.49 (s, 1H), 7.36-7.25 (m, 3H), 7.20 (t, J =7.7 Hz, 1H), 7.04-6.95 (m, 2H), 6.41 (d, J = 3.9 Hz, 1H), 5.11-5.03 (m,1H), 4.71-4.62 (m, 1H), 4.48 (s, 2H), 4.43-4.02 (m, 1H), 3.88-3.12 (m,3H), 2.09-1.87 (m, 4H), 1.27 (d, J = 6.0 Hz, 6H). 532 467.20 2.19 533462.30 2.44 534 439.28 2.04 535 483.10 1.47 1H NMR (400 MHz, DMSO) d8.12 (d, J = 3.2 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.47 (dd, J = 44.9,6.9 Hz, 1H), 7.38-7.24 (m, 2H), 7.20 (t, J = 7.0 Hz, 1H), 7.02 (d, J =4.0 Hz, 1H), 6.70-6.57 (m, 1H), 6.40 (t, J = 4.6 Hz, 1H), 4.57-4.36 (m,1H), 3.66-3.36 (m, 4H), 3.29-3.17 (m, 2H), 3.18-3.01 (m, 1H), 2.13 (dd,J = 25.2, 12.5 Hz, 1H), 2.08-1.97 (m, 2H), 1.97-1.77 (m, 5H). 536 444.502.18 1H NMR (400 MHz, DMSO) d 7.93 (d, J = 1.8, 1H), 7.75-7.69 (m, 2H),7.64 (d, J = 8.3, 1H), 7.50 (dd, J = 2.8, 1.3, 1H), 7.09 (dd, J = 9.6,2.8, 1H), 6.94 (td, J = 8.7, 2.8, 1H), 6.29 (t, J = 3.2, 1H), 6.17 (dd,J = 3.4, 1.3, 1H), 4.46-4.34 (m, 1H), 3.62-3.40 (m, 2H), 3.29-3.16 (m,1H), 2.15-1.83 (m, 4H), 1.46 (s, 9H). 537 448.20 2.00 538 431.20 2.08539 504.24 2.09 540 507.50 1.56 1H NMR (400 MHz, DMSO) d 8.00 (d, J =8.0 Hz, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.70-7.64 (m, 3H), 7.37-7.28 (m,3H), 7.26-7.18 (m, 1H), 6.47 (d, J = 4.0 Hz, 1H), 4.52-4.35 (m, 2H),3.60-3.12 (m, 5H), 2.85-2.75 (m, 2H), 2.15-2.02 (m, 3H), 1.95-1.85 (m,1H), 1.56-1.46 (m, 2H). 541 532.30 1.95 1H NMR (400 MHz, DMSO) d 8.03(s, 1H), 7.87 (d, J = 7.9 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.57 (d, J= 8.0 Hz, 1H), 7.37-7.11 (m, 3H), 7.03 (d, J = 3.7 Hz, 1H), 6.41 (d, J =3.7 Hz, 1H), 4.55-4.36 (m, 1H), 3.64-3.13 (m, 3H), 2.20-1.81 (m, 5H),0.54-0.33 (m, 4H). 542 454.19 1.58 543 480.30 2.24 1H NMR (400 MHz,DMSO) d 7.90 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.57-7.49(m, 2H), 7.46 (s, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.09 (dd, J = 16.6, 8.0Hz, 2H), 4.38 (d, J = 11.4 Hz, 1H), 4.10 (s, 3H), 3.58-3.46 (m, 2H),3.08 (d, J = 6.1 Hz, 2H), 2.65 (s, 3H), 2.08-1.79 (m, 4H), 1.18 (s, 3H),1.16 (s, 3H). 544 436.50 1.88 1H NMR (400 MHz, MeOD) d 7.70 (d, J = 8.0Hz, 1H), 7.48 (d, J = 4.6 Hz, 1H), 7.36-7.22 (m, 2H), 7.22-7.04 (m, 4H),5.11-5.01 (m, 1H), 4.03-3.96 (m, 3H), 3.71-3.37 (m, 4H), 2.24-2.13 (m,1H), 2.13-1.89 (m, 3H), 1.62-1.53 (m, 6H). 545 418.20 2.33 546 388.191.76 547 493.50 2.16 548 441.31 1.30 549 490.00 1.85 550 494.22 1.77 551429.70 2.15 552 454.50 1.65 553 448.50 4.80 554 495.00 1.94 555 429.702.27 1H NMR (400 MHz, CDCl3) d 7.22 (d, J = 7.4 Hz, 1H), 7.16 (s, 2H),7.04-6.84 (m, 7H), 6.21 (t, J = 3.2 Hz, 1H), 5.89 (d, J = 3.4 Hz, 1H),4.82 (br. s, 1H), 4.12 (br. s, 1H), 3.75 (s, 3H), 2.54 (q, J = 7.5 Hz,2H), 2.45-1.84 (m, 8H), 1.48 (s, 4H), 1.07 (t, J = 7.5 Hz, 3H). 556453.30 1.84 557 510.30 2.27 558 520.50 1.95 1H NMR (400 MHz, DMSO) d7.84 (d, J = 7.9 Hz, 1H), 7.63-7.54 (m, 2H), 7.49 (s, 1H), 7.46 (d, J =8.8 Hz, 1H), 7.35-7.25 (m, 2H), 7.25-7.17 (m, 1H), 7.03 (d, J = 3.9 Hz,1H), 6.42 (d, J = 4.0 Hz, 1H), 4.45 (d, J = 10.7 Hz, 1H), 3.61-3.40 (m,2H), 3.27-3.14 (m, 1H), 2.60 (s, 3H), 2.45 (d, J = 4.9 Hz, 3H),2.17-1.95 (m, 3H), 1.95-1.81 (m, 1H). 559 458.50 1.79 560 392.26 1.64561 457.10 2.35 562 384.10 2.16 563 379.50 2.01 564 442.20 6.16 1H NMR(400 MHz, CDCl3) d 8.41 (s, 1H), 7.71-7.58 (m, 3H), 7.22-7.04 (m, 3H),6.80 (d, J = 3.9 Hz, 1H), 6.07 (d, J = 3.9 Hz, 1H), 4.67 (d, J = 13.3Hz, 1H), 3.99 (d, J = 12.8 Hz, 1H), 3.65-3.52 (m, 1H), 3.33 (td, J =13.0, 2.9 Hz, 1H), 2.71 (q, J = 7.6 Hz, 2H), 2.18 (d, J = 15.2 Hz, 1H),2.13-1.98 (m, 3H), 1.27 (t, J = 7.6 Hz, 3H). 565 419.50 1.32 1H NMR (400MHz, CDCl3) d 7.58, 7.56, 7.53, 7.51, 7.41, 7.39, 7.27, 7.26, 7.25,7.24, 7.08, 7.05, 7.04, 7.01, 6.99, 6.53, 6.27, 6.25, 5.29, 5.27, 5.26,5.24, 5.22, 4.56, 4.52, 4.33, 4.15, 4.14, 3.95, 3.68, 3.65, 3.62, 3.59,3.50, 3.48, 3.46, 3.44, 3.35, 3.32, 3.29, 3.16, 3.14, 2.95, 2.21, 2.18,2.11, 2.07, 2.00, 1.94, 1.90, 1.86, 1.83, 1.80, 1.58, 1.37, 1.35, 1.22,1.20, 1.18, 0.06. 566 428.20 5.72 1H NMR (400 MHz, CDCl3) d 8.41 (s,1H), 7.77-7.56 (m, 3H), 7.24-7.05 (m, 3H), 6.80 (d, J = 3.9 Hz, 1H),6.08 (d, J = 3.9 Hz, 1H), 4.76-4.61 (m, 1H), 4.05-3.91 (m, 1H),3.69-3.52 (m, 1H), 3.43-3.24 (m, 1H), 2.39 (s, 3H), 2.28-1.98 (m, 4H).567 465.10 1.88 1H NMR (400 MHz, DMSO) d 7.71 (dd, J = 9.0, 5.6 Hz, 1H),7.50 (dd, J = 2.8, 1.3 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.11 (dd, J =9.6, 2.7 Hz, 1H), 7.05 (d, J = 1.2 Hz, 1H), 7.01 (dd, J = 7.9, 1.2 Hz,1H), 6.99-6.90 (m, 1H), 6.28 (t, J = 3.2 Hz, 1H), 6.18 (dd, J = 3.6, 1.3Hz, 1H), 4.52-4.26 (m, 1H), 3.83 (s, 3H), 3.70-3.40 (m, 3H), 3.13 (s,3H), 2.06-1.85 (m, 4H), 1.50 (s, 6H). 568 457.10 2.81 569 450.40 2.51570 458.50 6.03 571 444.40 1.51 1H NMR (400 MHz, CDCl3) d 8.12 (d, J =7.7 Hz, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H),7.24-7.19 (m, 1H), 7.17-7.10 (m, 2H), 7.02 (d, J = 4.0 Hz, 1H), 6.10 (d,J = 4.0 Hz, 1H), 4.67 (s, 1H), 3.78 (d, J = 11.1 Hz, 1H), 3.64 (d, J =11.1 Hz, 1H), 3.60-3.23 (m, 2H), 2.07 (s, 2H), 1.88 (s, 4H), 1.53 (s,3H). 572 501.30 1.82 573 431.14 2.94 574 458.25 1.77 575 441.20 2.18 576469.50 1.79 577 509.13 1.78 578 439.24 1.99 579 451.30 1.76 1H NMR (400MHz, CDCl3) d 7.97-7.91 (m, 2H), 7.64-7.59 (m, 2H), 7.39-7.32 (m, 1H),7.17-7.13 (m, 1H), 7.11-7.00 (m, 3H), 6.34 (t, J = 3.2 Hz, 1H),6.06-6.00 (m, 1H), 4.71-4.59 (m, 1H), 3.70-3.31 (m, 3H), 3.27-3.14 (m,1H), 2.29-1.76 (m, 4H), 1.31 (d, J = 6.9 Hz, 6H). 580 499.50 1.58 581452.00 1.89 582 466.30 1.52 1H NMR (400 MHz, DMSO) d 7.96 (d, J = 7.9Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.59-7.45 (m, 3H), 7.29 (t, J = 7.7Hz, 1H), 7.17-7.04 (m, 2H), 4.54-4.33 (m, 3H), 3.61-3.36 (m, 3H), 3.26(s, 3H), 2.68 (s, 3H), 2.10-1.80 (m, 4H), 1.38 (t, J = 7.2 Hz, 3H). 583432.70 1.54 584 520.30 1.96 585 449.30 5.90 586 496.50 1.52 1H NMR (400MHz, DMSO) d 7.83 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.45(s, 1H), 7.34 (s, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 8.0 Hz,1H), 7.15-7.06 (m, 2H), 4.45-4.31 (m, 1H), 4.10 (s, 3H), 3.97 (s, 3H),3.68 (septet, J = 6.7 Hz, 1H), 3.59-3.22 (m, 3H), 2.10-1.82 (m, 4H),1.17 (d, J = 6.9 Hz, 6H). 587 468.10 2.70 588 483.70 4.21 589 544.201.95 590 520.30 1.93 1H NMR (400 MHz, DMSO) d 7.85 (d, J = 8.2 Hz, 2H),7.72-7.65 (m, 3H), 7.58 (d, J = 8.0 Hz, 1H), 7.34-7.25 (m, 2H),7.25-7.17 (m, 1H), 7.03 (d, J = 3.9 Hz, 1H), 6.40 (d, J = 4.0 Hz, 1H),4.52-4.38 (m, 1H), 3.60-3.12 (m, 3H), 2.80 (q, J = 7.2 Hz, 2H),2.15-1.80 (m, 4H), 0.98 (t, J = 7.2 Hz, 3H). 591 400.31 1.17 592 479.301.82 593 458.20 2.41 1H NMR (400 MHz, CDCl3) d 7.56 (d, J = 7.7 Hz, 1H),7.38 (t, J = 8.1 Hz, 1H), 7.33-7.20 (m, 3H), 7.18-6.99 (m, 3H), 6.93 (t,J = 9.3 Hz, 1H), 4.67 (t, J = 15.1 Hz, 1H), 4.54-4.29 (m, 2H), 4.15 (s,3H), 3.71-3.48 (m, 1H), 3.48-3.23 (m, 2H), 2.20 (t, J = 11.8 Hz, 1H),2.10-1.64 (m, 3H). 594 494.50 1.76 1H NMR (400 MHz, MeOD) d 8.01 (d, J =8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.50(s, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 7.13 (t, J= 7.6 Hz, 1H), 5.18-5.01 (m, 1H), 3.75-3.62 (m, 1H), 3.62-3.40 (m, 4H),2.19-1.89 (m, 4H), 1.58 (d, J = 3.8 Hz, 6H), 1.29 (d, J = 6.9 Hz, 6H).595 400.30 1.30 596 463.00 1.86 597 411.20 2.12 598 432.50 1.47 599436.00 1.86 600 414.34 1.45 601 470.29 2.20 602 461.50 3.23 603 430.272.39 604 500.29 1.99 605 423.50 2.17 1H NMR (400 MHz, DMSO) d 7.71 (dd,J = 8.5, 4.5 Hz, 1H), 7.52 (d, J = 4.6 Hz, 1H), 7.37-7.23 (m, 2H),7.20-7.01 (m, 3H), 6.35-6.26 (m, 1H), 6.18 (dd, J = 9.0, 2.4 Hz, 1H),4.57-4.39 (m, 1H), 3.78-3.65 (m, J = 9.6 Hz, 3H), 3.54-3.11 (m, 3H),2.25 (s, 3H), 2.12-1.80 (m, 4H). 606 483.70 4.20 607 481.00 1.49 608432.70 1.89 609 467.50 1.93 610 446.30 1.97 611 431.06 2.72 612 465.102.01 613 466.30 4.17 614 471.30 1.62 615 511.24 2.14 616 509.32 2.04 617466.30 2.30 618 479.30 7.06 1H NMR (400 MHz, CDCl3) d 7.67 (d, J = 8.2Hz, 1H), 7.46-7.34 (m, 2H), 7.30 (t, J = 7.0 Hz, 1H), 7.25-7.05 (m, 4H),6.81 (d, J = 3.5 Hz, 1H), 6.56 (dd, J = 77.9, 70.7 Hz, 1H), 6.11-6.02(m, 1H), 4.72 (d, J = 10.8 Hz, 1H), 3.63-3.20 (m, 3H), 2.26-1.93 (m,4H), 1.60 (s, 1H). 619 444.10 1.85 620 420.10 1.83 621 519.50 6.38 622458.50 1.66 623 460.20 2.52 624 427.23 2.05 625 362.23 1.69 626 474.301.64 627 423.24 2.12 628 501.10 2.35 629 443.60 2.94 630 411.23 2.13 631489.50 2.62 632 493.50 1.89 633 442.50 1.70 634 505.50 1.90 635 453.202.91 636 478.10 6.14 637 448.50 1.43 638 416.21 2.36 639 461.22 2.40 640487.40 1.57 1H NMR (400 MHz, DMSO) d 7.57 (d, J = 7.7 Hz, 1H), 7.52 (d,J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.34-7.26 (m, 2H), 7.20 (t, J= 8.0 Hz, 1H), 7.02 (d, J = 4.0 Hz, 1H), 6.42 (d, J = 4.0 Hz, 1H), 4.98(s, 1H), 4.72 (t, J = 5.9 Hz, 1H), 4.41 (s, 2H), 3.44-3.39 (m, 2H),2.19-1.83 (m, 5H), 1.39 (s, 3H). 641 450.50 2.48 642 391.24 2.03 643480.20 1.70 1H NMR (400 MHz, DMSO) d 7.90 (d, J = 8.1 Hz, 2H), 7.77-7.70(m, 3H), 7.46 (s, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.14-7.04 (m, 2H),4.46-4.33 (m, 1H), 4.10 (s, 3H), 3.61-3.47 (m, 3H), 2.10-1.76 (m, 4H),1.26 (s, 9H). 644 414.50 1.51 645 427.23 2.02 646 450.30 1.50 1H NMR(400 MHz, DMSO) ? 7.76 (d, J = 29.4 Hz, 1H), 7.59 (dd, J = 7.5, 1.4 Hz,1H), 7.24-7.16 (m, 1H), 7.07-6.90 (m, 3H), 6.84 (d, J = 8.6 Hz, 1H),4.14 (d, J = 35.3 Hz, 2H), 3.87 (s, 3H), 3.82 (s, 6H), 3.76 (d, J = 4.8Hz, 3H), 3.31 (d, J = 13.6 Hz, 2H), 1.89 (dd, J = 46.8, 33.8 Hz, 4H).647 447.50 2.07 648 487.10 2.63 649 388.27 1.74 650 436.30 1.83 651411.10 1.53 652 411.20 1.42 653 478.20 2.59 654 488.20 1.81 655 442.002.19 1H NMR (400 MHz, CDCl3) d 8.14 (d, J = 8.0 Hz, 1H), 7.27-7.20 (m,3H), 7.19-7.12 (m, 2H), 7.04 (d, J = 4.0 Hz, 1H), 6.84 (d, J = 8.1 Hz,1H), 6.12 (d, J = 4.0 Hz, 1H), 4.74-4.25 (m, m, 2H), 3.44 (m, 3H), 2.22(s, 3H), 2.20-1.75 (m, 4H), 1.36 (d, J = 6.0 Hz, 6H). 656 472.39 2.29657 411.27 2.10 658 486.20 2.24 1H NMR (400 MHz, DMSO) d 7.57 (d, J =8.1 Hz, 1H), 7.50-7.42 (m, 2H), 7.30 (dtd, J = 9.3, 8.0, 1.5 Hz, 2H),7.25-7.17 (m, 1H), 7.01 (d, J = 4.0 Hz, 1H), 6.41 (d, J = 4.0 Hz, 1H),4.69 (hept, J = 6.1 Hz, 1H), 4.44 (d, J = 12.9 Hz, 1H), 3.93 (d, J =12.3 Hz, 1H), 3.31-3.13 (m, 1H), 2.34 (s, 3H), 2.11-1.83 (m, 4H), 1.32(t, J = 10.2 Hz, 6H). 659 422.04 1.92 660 453.50 1.67 661 407.50 2.03662 484.20 2.05 663 492.30 1.82 664 474.32 1.78 665 452.00 2.04 666450.10 1.09 667 472.22 1.61 668 478.30 2.02 669 447.50 2.11 670 410.501.59 1H NMR (400 MHz, CDCl3) d 7.74, 7.73, 7.52, 7.42, 7.41, 7.39, 7.39,7.28, 7.26, 7.10, 7.10, 7.04, 7.04, 7.02, 7.01, 6.56, 6.53, 6.34, 6.34,6.33, 6.03, 6.02, 4.12, 3.58, 3.48, 2.16, 2.12, 2.01, 1.97, 1.94, 1.57.671 386.30 1.59 1H NMR (400 MHz, DMSO) d 9.84 (s, 1H), 8.00 (d, J = 8.1Hz, 1H), 7.37-7.28 (m, 5H), 7.27-7.19 (m, 1H), 6.79 (d, J = 8.5 Hz, 2H),6.48 (d, J = 4.0 Hz, 1H), 2.11-1.89 (m, 4H). 672 390.21 1.57 1H NMR (400MHz, CDCl3) d 7.56 (d, J = 7.7 Hz, 1H), 7.43-7.19 (m, 4H), 6.89-7.16 (m,3H), 6.92 (d, J = 8.3 Hz, 1H), 4.67 (m, 1H), 4.16 (d, J = 2.0 Hz, 3H),3.86 (d, J = 4.5 Hz, 3H), 3.66-3.28 (m, 3H), 2.19 (d, J = 14.1 Hz, 1H),2.06-1.59 (m, 3H). 673 424.30 1.88 674 422.50 1.72 675 506.30 1.87 1HNMR (400 MHz, DMSO) d 7.84 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 8.1 Hz,2H), 7.65-7.43 (m, 2H), 7.34-7.25 (m, 2H), 7.25-7.17 (m, 1H), 7.03 (d, J= 4.0 Hz, 1H), 6.41 (d, J = 4.0 Hz, 1H), 4.51-4.38 (m, 1H), 3.61-3.12(m, 3H), 2.44 (s, 3H), 2.16-1.82 (m, 4H). 676 451.50 2.46 677 474.001.79 1H NMR (400 MHz, CDCl3) d 8.23 (s, 1H), 7.40 (d, J = 7.8 Hz, 1H),7.24 (d, J = 8.3 Hz, 2H), 7.20-7.04 (m, 3H), 6.83 (d, J = 8.1 Hz, 1H),6.28 (d, J = 3.5 Hz, 1H), 5.99 (d, J = 3.6 Hz, 1H), 5.89 (s, 1H), 4.77(d, J = 5.0 Hz, 2H), 4.57 (dt, J = 12.1, 6.0 Hz, 2H), 3.50 (s, 3H), 2.21(s, 3H), 2.00 (t, J = 23.8 Hz, 4H), 1.36 (d, J = 6.0 Hz, 6H). 678 475.301.69 679 510.00 1.91 680 490.50 1.49 681 481.50 2.23 682 485.50 2.07 683479.30 1.78 684 500.00 1.77 1H NMR (400 MHz, CDCl3) d 8.39 (d, J = 8.1Hz, 1H), 8.18-8.10 (m, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.80 (s, 1H), 7.24(dd, J = 14.9, 7.2 Hz, 1H), 7.19-7.11 (m, 2H), 7.03 (d, J = 4.0 Hz, 1H),6.12 (d, J = 4.0 Hz, 1H), 4.68 (s, 1H), 3.59 (s, 2H), 3.38 (d, J = 14.2Hz, 1H), 2.81 (s, 1H), 2.77 (s, 3H), 2.35-1.96 (m, 6H), 1.95-1.70 (m,2H). 685 549.60 1.87 1H NMR (400 MHz, DMSO) d 7.89 (d, J = 8.2 Hz, 2H),7.70 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.1 Hz, 1H), 7.36-7.14 (m, 3H),7.03 (d, J = 3.9 Hz, 1H), 6.40 (d, J = 3.9 Hz, 1H), 5.14-4.98 (m, 1H),4.55-4.36 (m, 1H), 3.58-3.37 (m, 4H), 3.30-3.10 (m, 1H), 2.20-1.77 (m,4H), 1.21 (s, 6H). 686 472.00 2.00 1H NMR (400 MHz, DMSO) d 8.00 (d, J =7.9 Hz, 1H), 7.33 (dd, J = 11.7, 4.1 Hz, 3H), 7.23 (dt, J = 8.7, 4.5 Hz,1H), 7.04 (dd, J = 14.8, 4.9 Hz, 2H), 6.48 (d, J = 4.1 Hz, 1H), 3.77 (s,3H), 3.47-3.21 (m, 98H), 2.52 (dd, J = 11.8, 10.2 Hz, 24H), 2.02 (s,5H), 1.29 (s, 9H). 687 688 481.40 2.79 689 432.70 1.90 690 495.18 1.93691 435.28 2.40 692 408.26 1.75 693 523.50 6.07 694 448.50 1.93 695519.26 2.42 696 541.21 2.20 697 437.50 2.00 1H NMR (400 MHz, DMSO) d7.71 (d, J = 8.6 Hz, 1H), 7.52 (dd, J = 2.9, 1.3 Hz, 1H), 7.29 (d, J =2.3 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.14 (dd, J = 8.6, 2.3 Hz, 1H),7.00-6.92 (m, 2H), 6.30 (t, J = 3.2 Hz, 1H), 6.20 (dd, J = 3.4, 1.3 Hz,1H), 4.51-4.30 (m, 1H), 3.82 (s, 3H), 3.67-3.41 (m, 2H), 3.29-3.15 (m,1H), 2.58 (q, J = 7.5 Hz, 2H), 2.06-1.86 (m, 4H), 1.13 (t, J = 7.5 Hz,3H). 698 472.30 2.03 699 408.50 1.81 700 390.50 3.87 701 388.30 2.40 702426.20 2.99 703 439.21 2.15 704 450.20 1.83 1H NMR (400 MHz, DMSO) d7.74 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.37 (t, J = 8.2 Hz, 1H), 7.28(t, J = 7.5 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H),6.94-6.91 (m, 1H), 6.90 (s, 1H), 4.39 (d, J = 13.0 Hz, 1H), 4.10 (s,3H), 3.58-3.43 (m, 1H), 3.42-3.38 (m, 1H), 3.31-3.20 (m, 1H), 2.07-1.97(m, 1H), 1.97-1.80 (m, 3H), 1.35 (s, 9H). 705 454.50 1.88 1H NMR (400MHz, MeOD) d 7.70 (d, J = 7.2 Hz, 1H), 7.56-7.45 (m, 2H), 7.43-7.33 (m,2H), 7.34-7.26 (m, 2H), 7.20-7.08 (m, 2H), 7.08-6.65 (m, 1H), 5.14-5.00(m, 1H), 3.71-3.55 (m, 1H), 3.49-3.36 (m, 3H), 2.24-1.88 (m, 4H),1.62-1.52 (m, 6H). 706 454.50 1.90 707 413.20 1.86 708 413.27 2.45 709432.30 2.01 710 432.40 3.14 711 432.70 1.62 1H NMR (400 MHz, CDCl3) d7.57 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.1 Hz,2H), 7.32-7.20 (m, 2H), 7.06 (dd, J = 15.4, 7.8 Hz, 2H), 4.60 (m, 1H),4.42 (m, 1H), 4.18 (s, 3H), 3.80-3.26 (m, 3H), 2.32-1.71 (m, 7H), 0.96(d, 6.2 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H). 712 501.30 2.55 713 460.501.75 714 467.30 1.53 1H NMR (400 MHz, CDCl3) d 7.84 (d, J = 8.1 Hz, 2H),7.61 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 7.7 Hz, 1H), 7.30-7.23 (m, 2H),7.11-7.03 (m, 2H), 4.77-4.49 (m, 1H), 4.16 (s, 3H), 3.77-3.31 (m, 3H),2.73 (s, 6H), 2.34-1.71 (m, 4H). 715 434.17 2.23 716 462.20 2.73 717417.50 6.92 718 410.50 1.65 1H NMR (400 MHz, CDCl3) d 8.85, 7.52, 7.34,7.33, 7.33, 7.32, 7.31, 7.30, 7.29, 7.28, 7.26, 7.11, 7.11, 7.10, 7.09,7.04, 7.04, 7.02, 7.02, 6.61, 6.59, 6.35, 6.34, 6.33, 6.16, 6.14, 6.13,6.11, 6.04, 6.03, 6.02, 4.64, 4.63, 4.61, 3.97, 3.70, 3.66, 3.64, 3.64,3.61, 3.60, 3.58, 3.57, 3.56, 3.55, 3.52, 3.49, 3.39, 3.38, 3.35, 3.35,3.34, 3.33, 3.32, 3.31, 3.30, 3.27, 3.27, 2.25, 2.22, 2.15, 2.14, 2.11,2.08, 2.08, 2.02, 2.01, 2.00, 1.99, 1.98, 1.95, 1.94, 1.93, 1.92, 1.91,1.90, 1.88, 1.87, 1.85, 1.83, 1.81, 1.80, 1.78, 1.76, 1.75, 1.70, 1.14.719 415.26 1.98 720 465.18 2.20 721 491.50 1.83 1H NMR (400 MHz, CDCl3)d 8.13 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.2Hz, 2H), 7.22 (d, J = 7.5 Hz, 1H), 7.15 (t, J = 7.3 Hz, 2H), 7.02 (d, J= 4.0 Hz, 1H), 6.11 (d, J = 4.0 Hz, 1H), 4.75-4.63 (m, 1H), 4.26 (d, J =7.6 Hz, 1H), 3.65-3.54 (m, 2H), 3.54-3.46 (m, 1H), 3.42-3.27 (m, 1H),2.32-2.16 (m, 1H), 2.14-1.95 (m, J = 10.9 Hz, 2H), 1.91-1.77 (m, 1H),1.11 (d, J = 6.5 Hz, 6H). 722 471.50 1.96 1H NMR (400 MHz, CDCl3) d 7.67(d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H),7.22-7.03 (m, 3H), 6.81 (d, J = 3.9 Hz, 1H), 6.06 (d, J = 3.9 Hz, 1H),4.65 (s, 1H), 4.12 (q, J = 7.1 Hz, 1H), 3.84-3.16 (m, 5H), 2.31-1.67 (m,6H), 1.66-1.47 (m, 9H). 723 509.60 3.38 724 409.50 2.06 1H NMR (400 MHz,DMSO) d 7.71 (d, J = 8.6 Hz, 1H), 7.52 (dd, J = 2.9, 1.4 Hz, 1H), 7.36(t, J = 7.8 Hz, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 8.6, 2.3Hz, 1H), 7.04-6.95 (m, 3H), 6.30 (t, J = 3.2 Hz, 1H), 6.21 (dd, J = 3.4,1.3 Hz, 1H), 4.49-4.33 (m, 1H), 3.79 (s, 3H), 3.60-3.15 (m, 3H),2.12-1.80 (m, 4H). 725 463.50 1.98 726 472.50 1.58 727 447.10 2.63 H NMR(400.0 MHz, DMSO) d 7.68-7.65 (m, 1H), 7.50-7.48 (m, 1H), 7.19-6.90 (m,6H), 6.29-6.28 (m, 1H), 6.18-6.17 (m, 1H), 4.60-4.10 (m, 1H), 3.98-3.08(m, 6H), 1.96 (s, 4H) and 1.29 (s, 9H) ppm. 728 424.50 1.66 1H NMR (400MHz, CDCl3) d 7.56, 7.55, 7.54, 7.54, 7.37, 7.37, 7.36, 7.35, 7.31,7.26, 7.24, 7.08, 7.08, 7.01, 7.01, 6.99, 6.98, 6.33, 6.32, 6.31, 6.27,6.25, 6.23, 6.07, 6.06, 5.30, 4.66, 4.63, 4.02, 3.58, 3.45, 3.42, 3.32,3.29, 3.26, 2.17, 2.14, 2.10, 2.09, 2.07, 2.04, 2.01, 1.59, 1.37, 1.35,1.33, 1.21, 1.19, 0.07. 729 493.25 2.22 730 420.30 1.73 731 509.50 2.11732 443.40 6.14 1H NMR (400 MHz, CDCl3) d 7.67 (d, J = 8.1 Hz, 1H), 7.15(ddd, J = 26.0, 23.5, 13.3 Hz, 5H), 6.81 (d, J = 2.7 Hz, 1H), 6.72 (s,1H), 6.06 (s, 1H), 3.47 (d, J = 19.7 Hz, 3H), 2.23 (s, 3H), 2.08 (s,2H), 2.02-1.79 (m, 2H). 733 446.00 1.45 734 473.30 4.94 735 417.00 2.24736 488.30 1.85 737 451.30 2.51 738 422.50 1.70 1H NMR (400 MHz, CDCl3)d 7.57, 7.55, 7.52, 7.31, 7.29, 7.27, 7.26, 7.26, 7.23, 7.13, 7.11,7.09, 7.06, 7.05, 7.03, 7.01, 6.99, 6.97, 6.95, 4.67, 4.64, 4.15, 4.13,4.11, 4.09, 3.94, 3.61, 3.50, 3.49, 3.47, 3.45, 3.34, 2.22, 2.18, 2.04,2.01, 1.98, 1.97, 1.94, 1.93, 1.91, 1.90, 1.78, 1.57, 1.48, 1.46, 1.44,1.25, 1.22, 1.21, 1.19. 739 427.18 2.21 740 426.00 1.42 741 410.30 1.601H NMR (400 MHz, CDCl3) d 7.52, 7.38, 7.36, 7.28, 7.26, 7.10, 7.09,7.04, 7.03, 7.02, 7.01, 6.55, 6.35, 6.34, 6.33, 6.21, 6.19, 6.03, 6.03,5.30, 4.60, 4.56, 4.13, 4.11, 3.67, 3.60, 3.56, 3.29, 3.26, 3.23, 2.20,2.17, 2.08, 2.05, 1.96, 1.87, 1.55, 1.28, 1.26. 742 480.50 1.90 1H NMR(400 MHz, DMSO) d 7.52 (s, 1H), 7.48 (dd, J = 9.4, 2.3 Hz, 1H),7.20-7.09 (m, 2H), 7.02 (s, 1H), 6.99 (s, 2H), 4.60 (hept, J = 5.8 Hz,1H), 4.45 (q, J = 7.2 Hz, 2H), 4.36-4.18 (m, 1H), 3.76 (s, 3H),3.70-3.39 (m, 2H), 3.28-3.13 (m, 1H), 2.02-1.84 (m, 4H), 1.37 (t, J =7.2 Hz, 3H), 1.26 (d, J = 6.0 Hz, 6H). 743 515.20 2.33 744 442.18 2.52745 446.50 5.70 1H NMR (400 MHz, DMSO) d 7.74 (d, J = 7.6 Hz, 1H), 7.48(s, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.16-7.05 (m, 4H), 4.31 (s, 1H),4.23-4.16 (m, 1H), 4.10 (s, 3H), 3.44 (d, J = 53.4 Hz, 2H), 2.23 (s,6H), 1.92 (d, J = 6.6 Hz, 4H), 1.24 (d, J = 6.1 Hz, 6H). 746 404.70 1.351H NMR (400 MHz, CDCl3) d 7.57 (d, J = 7.7 Hz, 1H), 7.41 (d, J = 7.5 Hz,1H), 7.33-7.11 (m, 4H), 7.10-7.02 (m, 2H), 4.78-4.65 (m, 3H), 4.15 (s,3H), 3.57-3.48 (m, 1H), 3.45-3.31 (m, 2H), 2.33 (d, J = 21.1 Hz, 3H),2.26-2.19 (m, 1H), 2.04-1.88 (m, 2H), 1.84-1.64 (m, 2H). 747 450.30 1.47748 420.26 1.77 749 429.50 2.02 750 432.30 2.22 751 539.50 6.58 752480.30 2.05 1H NMR (400 MHz, CDCl3) d 7.87 (d, J = 7.7 Hz, 1H), 7.58 (d,J = 11.1 Hz, 1H), 7.47-7.35 (m, 2H), 7.35-7.25 (m, 2H), 7.21 (t, J = 8.7Hz, 1H), 7.11-6.98 (m, 2H), 6.58 (t, J = 74.7 Hz, 1H), 4.78-4.62 (m,1H), 3.71-3.51 (m, 1H), 3.47-3.26 (m, 2H), 2.37-2.22 (m, 1H), 2.16-1.81(m, 3H). 753 427.25 2.39 754 446.30 2.46 755 472.00 2.10 756 512.21 1.83757 480.22 1.51 758 473.50 4.90 759 539.50 2.07 760 522.24 1.80 761448.30 1.70 762 428.50 1.71 1H NMR (400 MHz, CDCl3) d 8.12 (d, J = 7.5Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 7.29-7.09(m, 3H), 7.01 (t, J = 5.6 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H), 4.67 (m,1H), 3.74 (m, 1H), 3.49 (m, 1H), 3.32 (m, 1H), 1.75-2.25 (m, 4H), 1.73(s, 1H), 1.58 (s, 6H). 763 408.24 1.83 764 417.13 2.89 765 427.25 2.67766 406.50 1.84 767 479.30 1.49 768 511.50 1.69 769 432.50 2.00 1H NMR(400 MHz, CDCl3) d 8.19-8.02 (m, 1H), 7.29-6.89 (m, 10H), 6.09 (t, J =3.5 Hz, 1H), 4.74 (d, J = 13.4 Hz, 1H), 4.49-3.96 (m, 2H), 3.69-3.26 (m,3H), 3.24 (d, J = 13.2 Hz, 1H), 2.21 (d, J = 15.7 Hz, 2H), 2.10-1.87 (m,2H), 1.74 (d, J = 12.5 Hz, 0H), 1.55 (d, J = 3.0 Hz, 1H), 1.38 (td, J =6.9, 3.7 Hz, 3H). 770 446.30 2.05 1H NMR (400 MHz, CDCl3) d 8.12 (d, J =7.5 Hz, 1H), 7.25 (d, J = 11.0 Hz, 3H), 7.14 (ddd, J = 18.7, 16.0, 7.7Hz, 4H), 6.99 (dt, J = 22.4, 5.5 Hz, 3H), 6.11 (s, 1H), 4.73 (d, J =10.9 Hz, 1H), 4.60-4.46 (m, 1H), 3.52 (s, 2H), 3.28 (s, 1H), 2.22 (s,0H), 2.28-2.12 (m, 1H), 2.13-1.90 (m, 3H), 1.55 (s, 1H), 1.36 (d, J =6.0 Hz, 5H). 771 420.30 1.63 772 773 408.22 1.74 774 404.30 1.63 775515.50 2.14 776 401.22 2.21 777 469.40 2.92 778 527.30 6.81 779 414.252.43 780 469.50 2.15 1H NMR (400 MHz, CDCl3) d 7.74 (s, 1H), 7.66 (dd, J= 8.6, 1.7 Hz, 1H), 7.31 (d, J = 7.4 Hz, 1H), 7.10-6.97 (m, 5H), 6.29(t, J = 3.2 Hz, 1H), 6.01-5.94 (m, 1H), 4.88 (br. s, 1H), 4.13 (br. s,1H), 3.92 (s, 3H), 2.59-2.15 (m, 5H), 2.06 (br. s, 3H), 1.57 (s, 3H).781 476.30 1.64 1H NMR (400 MHz, CDCl3) d 8.22-8.05 (m, 1H), 7.50 (q, J= 8.2 Hz, 4H), 7.27-7.19 (m, 4H), 7.19-7.09 (m, 2H), 7.01 (t, J = 6.2Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H), 4.67 (s, 1H), 4.31-4.12 (m, 1H), 3.62(d, J = 39.1 Hz, 2H), 3.33 (s, 1H), 2.72 (d, J = 20.1 Hz, 3H), 2.12 (d,J = 47.3 Hz, 2H), 2.01 (s, 4H), 1.82 (t, J = 13.7 Hz, 4H), 1.58 (d, J =20.4 Hz, 3H). 782 458.50 1.55 1H NMR (400 MHz, CDCl3) d 8.15-8.07 (m,1H), 7.50 (d, J = 8.0 Hz, 1H), 7.25-7.16 (m, 3H), 7.16-7.08 (m, 2H),7.02 (d, J = 4.0 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H), 4.74-4.57 (m, 1H),4.00 (d, J = 11.1 Hz, 1H), 3.85-3.71 (m, 1H), 3.69 (d, J = 11.1 Hz, 1H),3.63-3.23 (m, J = 86.9 Hz, 2H), 2.56 (s, 3H), 2.23-2.07 (m, 2H),1.99-1.72 (m, 5H), 1.58 (s, 3H). 783 497.50 2.02 784 462.50 1.67 1H NMR(400 MHz, CDCl3) d 8.21-8.06 (m, 1H), 7.84-7.80 (m, 2H), 7.48-7.35 (m,1H), 7.29-7.18 (m, 1H), 7.19-7.08 (m, 2H), 7.02 (d, J = 3.9 Hz, 1H),6.12-6.08 (m, 1H), 4.75 (d, J = 13.8 Hz, 1H), 3.57-3.48 (m, 1H),3.42-3.21 (m, 2H), 3.05 (s, 3H), 2.44 (d, J = 13.0 Hz, 3H), 2.28-2.21(m, 1H), 2.15-1.88 (m, 2H), 1.84-1.69 (m, 1H). 785 544.20 1.95 786431.15 2.18 787 431.19 2.17 788 476.40 3.02 789 460.50 1.46 790 395.111.86 791 449.10 2.35 H NMR (400.0 MHz, DMSO) d 7.67-7.65 (m, 1H),7.50-7.49 (m, 1H), 7.17-6.99 (m, 6H), 6.29-6.26 (m, 1H), 6.18-6.17 (m,1H), 4.35 (s, 1H), 4.12-4.10 (m, 2H), 3.82-3.78 (m, 3H), 3.67-3.65 (m,2H), 3.40 (s, 3H), 3.33-3.30 (m, 3H) and 1.95 (s, 4H) ppm. 792 451.301.98 793 471.30 1.88 794 521.30 1.84 1H NMR (400 MHz, DMSO) d 7.97 (d, J= 8.1 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.1 Hz, 1H),7.34-7.16 (m, 3H), 7.03 (d, J = 4.0 Hz, 1H), 6.40 (d, J = 4.0 Hz, 1H),4.90 (t, J = 4.9 Hz, 1H), 4.52-4.37 (m, 1H), 3.75-3.65 (m, 2H),3.58-3.36 (m, 4H), 3.28-3.15 (m, 1H), 2.20-1.77 (m, 4H). 795 457.00 2.13796 450.50 1.52 797 388.30 2.41 798 415.19 2.09 799 452.00 2.01 800450.27 1.76 801 418.50 1.75 1H NMR (400 MHz, DMSO) d 7.74 (d, J = 7.7Hz, 1H), 7.47 (s, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.13 (s, 4H), 4.33 (s,1H), 4.10 (s, 3H), 3.68 (s, 5H), 2.25 (s, 6H), 2.07 (s, 1H), 1.91 (s,4H). 802 432.70 3.15 803 435.50 7.08 804 537.50 2.08 1H NMR (400 MHz,DMSO) d 7.93 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.58 (dd, J= 9.0, 5.2 Hz, 1H), 7.29 (dd, J = 9.1, 2.7 Hz, 1H), 7.10 (td, J = 8.7,2.9 Hz, 1H), 7.03 (d, J = 3.9 Hz, 1H), 6.41 (d, J = 3.9 Hz, 1H),4.54-4.37 (m, 1H), 3.64-3.16 (m, 4H), 2.18-1.81 (m, 4H), 1.17 (d, J =6.8 Hz, 6H). 805 472.30 3.09 806 434.20 1.94 807 422.04 1.88 808 491.151.91 809 404.20 1.77 810 442.50 2.02 1H NMR (400 MHz, CDCl3) d 8.12 (d,J = 7.6 Hz, 1H), 7.46-7.38 (m, 4H), 7.22 (t, J = 7.3 Hz, 1H), 7.16-7.11(m, 2H), 7.02 (d, J = 4.0 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H), 5.19 (d, J= 11.0 Hz, 2H), 4.97 (s, 1H), 3.83-3.25 (m, 3H), 2.26-1.79 (m, 5H), 1.60(s, 6H). 811 426.10 1.68 812 451.20 2.38 1H NMR (400 MHz, DMSO) d 7.71(dd, J = 8.9, 5.6 Hz, 1H), 7.53-7.47 (m, 1H), 7.11 (dd, J = 9.6, 2.6 Hz,1H), 7.05-6.98 (m, 3H), 6.94 (td, J = 8.8, 2.7 Hz, 1H), 6.28 (t, J = 3.1Hz, 1H), 6.18 (d, J = 3.4 Hz, 1H), 4.58-4.02 (m, 1H), 3.94 (t, J = 6.5Hz, 2H), 3.79 (s, 3H), 3.59-3.09 (m, 3H), 2.06-1.86 (m, 4H), 1.73(sextet, J = 6.8 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H). 813 518.50 1.80 814458.28 2.17 815 483.50 1.97 1H NMR (400 MHz, CDCl3) d 7.67 (d, J = 8.1Hz, 1H), 7.53-7.35 (m, 4H), 7.23-7.03 (m, 3H), 6.81 (d, J = 3.9 Hz, 1H),6.06 (d, J = 3.9 Hz, 1H), 4.64 (bs, 1H), 4.03 (d, J = 8.3 Hz, 1H),3.81-3.23 (m, 3H), 2.32-1.70 (m, 5H), 1.29-1.05 (m, 1H), 0.72-0.28 (m,4H). 816 399.26 1.67 817 431.70 2.10 818 485.00 2.38 819 521.00 1.85 1HNMR (400 MHz, CDCl3) d 8.59 (d, J = 8.3 Hz, 1H), 7.69 (s, 1H), 7.64 (d,J = 8.5 Hz, 1H), 7.24 (t, J = 7.2 Hz, 2H), 7.19-7.12 (m, 2H), 7.04 (d, J= 8.5 Hz, 1H), 6.15 (d, J = 4.1 Hz, 1H), 4.57 (s, 1H), 3.94 (s, 3H),3.47 (s, 3H), 3.08 (s, 3H), 2.27-1.67 (m, 4H). 820 491.30 1.57 821466.30 2.21 822 462.50 2.09 823 454.33 2.16 824 495.50 1.60 825 463.502.20 826 468.00 1.98 827 447.50 1.54 1H NMR (400 MHz, CDCl3) d 7.35 (d,J = 7.4 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.15 (dd, J = 2.8, 1.3 Hz,1H), 7.11-6.99 (m, 5H), 6.33 (t, J = 3.2 Hz, 1H), 6.04 (dd, J = 3.5, 1.3Hz, 1H), 5.02 (d, J = 7.2 Hz, 2H), 4.86 (d, J = 7.1 Hz, 2H), 4.72-4.54(m, 1H), 3.90 (s, 3H), 3.78-3.24 (m, 3H), 2.35-1.76 (m, 4H). 828 444.302.54 829 505.50 1.89 830 419.20 1.66 831 420.30 1.75 832 520.30 1.98 1HNMR (400 MHz, CDCl3) d 8.10 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 8.3 Hz,2H), 7.61 (d, J = 8.3 Hz, 2H), 7.17 (s, 1H), 7.09 (d, J = 8.3 Hz, 1H),7.02 (d, J = 4.0 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H), 4.75-4.63 (m, 1H),4.45 (s, 2H), 3.64-3.46 (m, 2H), 3.43 (s, 3H), 3.41-3.29 (m, 1H),3.26-3.17 (m, 1H), 2.29-2.19 (m, 1H), 2.10-1.99 (m, 2H), 1.81 (s, 1H),1.31 (d, J = 6.9 Hz, 6H). 833 407.15 2.20 834 433.20 1.72 835 495.211.93 836 513.50 8.20 837 461.50 1.88 838 458.50 5.96 839 428.00 2.08 1HNMR (400 MHz, CDCl3) d 8.05 (d, J = 8.0 Hz, 1H), 7.18-7.02 (m, 4H), 6.95(d, J = 4.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 6.03 (d, J = 4.0 Hz, 1H),4.59 (s, 1H), 3.78 (s, 3H), 3.37 (d, J = 81.3 Hz, 3H), 2.57 (q, J = 7.5Hz, 2H), 2.35-1.60 (m, 4H), 1.11 (t, J = 7.5 Hz, 3H). 840 547.50 5.88 1HNMR (400 MHz, DMSO) d 8.08-7.93 (m, 2H), 7.84-7.69 (m, 2H), 7.57 (d, J =8.1 Hz, 1H), 7.38-7.12 (m, 3H), 7.11-6.96 (m, 1H), 6.48-6.31 (m, 1H),4.53-4.18 (m, 2H), 4.07-3.97 (m, 1H), 3.88-3.71 (m, 2H), 3.69-3.59 (m,1H), 3.60-3.37 (m, 2H), 3.31-3.13 (m, 1H), 2.23-1.78 (m, 6H). 841 416.501.84 842 450.97 3.18 843 450.97 3.12 844 505.30 5.49 1H NMR (400 MHz,DMSO) d 8.00 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.73-7.60(m, 3H), 7.34 (d, J = 4.0 Hz, 1H), 7.31 (d, J = 4.2 Hz, 2H), 7.27-7.20(m, 1H), 6.47 (d, J = 4.0 Hz, 1H), 4.57-4.36 (m, 1H), 3.60-3.37 (m, 2H),3.28-3.09 (m, 1H), 2.18-1.77 (m, 4H), 1.10 (s, 9H). 845 408.20 2.19 846473.30 1.83 1H NMR (400 MHz, DMSO) d 7.57 (d, J = 8.1 Hz, 1H), 7.42 (d,J = 8.6 Hz, 2H), 7.38-7.16 (m, 3H), 7.01 (d, J = 4.0 Hz, 1H), 6.99 (d, J= 8.6 Hz, 2H), 6.41 (d, J = 4.0 Hz, 1H), 4.88 (t, J = 5.5 Hz, 1H),4.49-4.09 (m, 1H), 4.03 (t, J = 4.9 Hz, 2H), 3.80-3.66 (m, 2H),3.66-3.15 (m, 3H), 2.15-1.80 (m, 4H). 847 848 433.50 1.78 849 427.501.50 1H NMR (400 MHz, CDCl3) d 8.57 (s, 1H), 8.06 (d, J = 7.5 Hz, 1H),7.65 (dd, J = 8.2, 2.3 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.18-7.03 (m,3H), 6.95 (d, J = 4.0 Hz, 1H), 6.03 (d, J = 4.0 Hz, 1H), 4.69-4.48 (m,1H), 3.81-3.11 (m, 3H), 2.24-1.72 (m, 4H), 1.31 (s, 9H). 850 447.30 2.07851 530.00 1.82 1H NMR (400 MHz, CDCl3) d 7.29 (d, J = 5.9 Hz, 3H), 7.12(d, J = 2.1 Hz, 2H), 7.09-6.99 (m, 3H), 6.91 (d, J = 8.2 Hz, 1H), 6.36(t, J = 3.2 Hz, 1H), 6.06 (d, J = 3.2 Hz, 1H), 4.61 (s, 1H), 4.48 (t, J= 5.3 Hz, 2H), 3.89 (s, 3H), 3.88-3.28 (m, J = 5.2 Hz, 5H), 3.24 (q, J =7.4 Hz, 2H), 3.20 (s, 3H), 2.82 (s, 2H), 2.12-1.75 (m, 4H), 1.41 (t, J =7.3 Hz, 2H). 852 431.70 2.38 853 420.50 1.38 1H NMR (400 MHz, CDCl3) d7.57 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.35-7.21 (m, 3H),7.17 (t, J = 7.9 Hz, 1H), 7.13-7.00 (m, 2H), 4.88-4.80 (m, 1H),4.77-4.54 (m, 2H), 4.15 (d, J = 3.1 Hz, 3H), 3.90 (d, J = 11.6 Hz, 3H),3.72-3.24 (m, 3H), 2.32-1.60 (m, 5H). 854 441.50 1.30 1H NMR (400 MHz,DMSO) d 9.30 (bs, 1H), 9.14 (bs, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.45 (d,J = 8.6 Hz, 2H), 7.37-7.29 (m, 3H), 7.28-7.16 (m, 1H), 6.93 (d, J = 8.6Hz, 2H), 6.47 (d, J = 4.0 Hz, 1H), 5.17-5.09 (m, 1H), 4.49-4.40 (m, 3H),4.04-3.95 (m, 3H), 2.12-1.90 (m, 4H). 855 449.10 2.22 1H NMR (400 MHz,DMSO) d 7.71 (dd, J = 8.9, 5.6 Hz, 1H), 7.49 (dd, J = 2.8, 1.3 Hz, 1H),7.27 (d, J = 7.9 Hz, 1H), 7.10 (dd, J = 9.6, 2.8 Hz, 1H), 7.01 (d, J =1.3 Hz, 1H), 6.98-6.90 (m, 2H), 6.28 (t, J = 3.2 Hz, 1H), 6.18 (dd, J =3.4, 1.2 Hz, 1H), 4.51-4.26 (m, 1H), 3.84 (s, 3H), 3.73-3.40 (m, 3H),2.05-1.85 (m, 4H), 1.34 (s, 9H). 856 394.50 1.39 1H NMR (400 MHz, DMSO)d 10.41 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.46 (s, 1H), 7.32-7.23 (m,2H), 7.15-7.04 (m, 3H), 6.98 (t, J = 8.5 Hz, 1H), 4.10 (s, 3H),3.52-3.19 (m, 4H), 1.99-1.85 (m, 4H). 857 477.00 2.04 1H NMR (400 MHz,DMSO) d 7.77 (d, J = 8.6 Hz, 1H), 7.74-7.67 (m, 2H), 7.56-7.50 (m, 1H),7.33 (d, J = 8.6 Hz, 1H), 7.31-7.27 (m, 1H), 7.14 (dd, J = 8.8, 2.0 Hz,1H), 6.30 (t, J = 2.6 Hz, 1H), 6.22-6.16 (m, 1H), 4.65-4.21 (m, 1H),3.94 (s, 3H), 3.74-3.38 (m, 3H), 2.06-1.83 (m, 4H). 858 443.12 2.15 859452.30 1.46 1H NMR (400 MHz, DMSO) d 7.96 (d, J = 8.0 Hz, 2H), 7.79-7.68(m, 3H), 7.46 (s, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.16-7.03 (m, 2H),4.47-4.32 (m, 1H), 4.10 (s, 3H), 3.62-3.20 (m, 3H), 3.35 (q, J = 7.4 Hz,2H), 2.10-1.82 (m, 4H), 1.12 (t, J = 7.3 Hz, 3H). 860 430.70 1.77 861413.27 2.23 862 471.19 1.69 863 474.50 1.81 864 442.50 1.53 1H NMR (400MHz, CDCl3) d 8.17-8.03 (m, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.41 (t, J =9.3 Hz, 2H), 7.25-7.18 (m, 1H), 7.18-7.08 (m, 2H), 7.02 (d, J = 4.0 Hz,1H), 6.09 (d, 4.0 Hz, 1H), 4.95 (d, J = 7.3 Hz, 2H), 4.82 (d, 7.3 Hz,2H), 4.67 (bs, 1H), 3.81-3.21 (m, 4H), 2.34-1.50 (m, 4H). 865 418.002.02 1H NMR (400 MHz, CDCl3) d 8.20-8.08 (m, 1H), 7.45 (s, 1H),7.32-7.21 (m, 4H), 7.16 (dd, J = 7.0, 5.5 Hz, 2H), 7.04 (d, J = 4.0 Hz,1H), 6.13 (d, J = 4.0 Hz, 1H), 4.67 (s, 1H), 3.98-3.04 (m, 3H), 2.42 (s,3H), 2.33-1.71 (m, 5H). 866 434.20 1.93 867 414.50 1.47 1H NMR (400 MHz,DMSO) d 8.10 (s, 1H), 7.76-7.69 (m, 2H), 7.55-7.42 (m, 2H), 7.28 (t, J =7.7 Hz, 1H), 7.21 (d, J = 7.0 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.07(t, J = 7.6 Hz, 1H), 4.63-4.31 (m, 1H), 4.09 (s, 3H), 4.08 (s, 3H),3.64-3.19 (m, 3H), 2.18-1.67 (m, 4H). 868 390.30 2.35 869 490.00 1.82870 413.30 2.19 1H NMR (400 MHz, CDCl3) d 7.46-7.27 (m, 7H), 7.12 (d, J= 2.1 Hz, 2H), 7.04 (dd, J = 8.5, 2.2 Hz, 1H), 6.36 (t, J = 3.2 Hz, 1H),6.07 (d, J = 3.4 Hz, 1H), 5.32 (s, 1H), 4.65 (br. s, 1H), 3.64 (br. s,2H), 3.35 (br. s, 1H), 2.20 (br. s, 1H), 2.05 (br.s, 2H), 1.86 (br. s,1H), 1.59 (s, 6H).

Assays for Detecting and Measuring NaV Inhibition Properties of Compound

E-VIPR Optical Membrane Potential Assay Method with ElectricalStimulation

Sodium channels are voltage-dependent proteins that can be activated byinducing membrane voltage changes by applying electric fields. Theelectrical stimulation instrument and methods of use are described inIon Channel Assay Methods PCT/US01/21652, herein incorporated byreference and are referred to as E-VIPR. The instrument comprises amicrotiter plate handler, an optical system for exciting the coumarindye while simultaneously recording the coumarin and oxonol emissions, awaveform generator, a current- or voltage-controlled amplifier, and adevice for inserting electrodes in well. Under integrated computercontrol, this instrument passes user-programmed electrical stimulusprotocols to cells within the wells of the microtiter plate.

24 hours before the assay on E-VIPR, HEK cells expressing human NaVsubtype, like NaV 1.7, are seeded in 384-well poly-lysine coated platesat 15,000-20,000 cells per well. Other subtypes are performed in ananalogous mode in a cell line expressing the NaV of interest. HEK cellsare grown in media (exact composition is specific to each cell type andNaV subtype) supplemented with 10% FBS (Fetal Bovine Serum, qualified;GibcoBRL #16140-071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL#15140-122). Cells are grown in vented cap flasks, in 90% humidity and10% CO₂, to 100% confluence. They are usually split by trypsinization1:10 or 1:20, depending on scheduling needs, and grown for 2-3 daysbefore the next split.

Reagents and Solutions

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

Compound Plates: 384-well round bottom plate, e.g. Corning 384-wellPolypropylene Round Bottom #3656

Cell Plates: 384-well tissue culture treated plate, e.g. Greiner#781091-1B

10 mM DiSBAC₆(3) (Aurora #00-100-010) in dry DMSO

10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO

200 mM ABSC1 in H₂O

Bath1 buffer. Glucose 10 mM (1.8 g/L), Magnesium Chloride (Anhydrous), 1mM (0.095 g/L), Calcium Chloride, 2 mM (0.222 g/L), HEPES 10 mM (2.38g/L), Potassium Chloride, 4.5 mM (0.335 g/L), Sodium Chloride 160 mM(9.35 g/L).

Hexyl Dye Solution: Bath1 Buffer+0.5% β-cyclodextrin (make this prior touse, Sigma #C4767), 8 μM CC2-DMPE+DiSBAC₆(3). To make the solution Addvolume of 10% Pluronic F127 stock equal to volumes ofCC2-DMPE+DiSBAC₆(3). The order of preparation is first mix Pluronic andCC2-DMPE, then add DiSBAC₆(3) while vortexing, then addBath1+β-Cyclodextrin.

Assay Protocol

1) Pre-spot compounds (in neat DMSO) into compound plates. Vehiclecontrol (neat DMSO), the positive control (20 mM DMSO stock tetracaine,125 μM final in assay) and test compounds are added to each well at 160×desired final concentration in neat DMSO. Final compound plate volumewill be 80 μL (80-fold intermediate dilution from 1 μL DMSO spot;160-fold final dilution after transfer to cell plate). Final DMSOconcentration for all wells in assay is 0.625%.

2) Prepare Hexyl Dye Solution.

3) Prepare cell plates. On the day of the assay, medium is aspirated andcells are washed three times with 100 μL of Bathl Solution, maintaining25 μL residual volume in each well.

4) Dispense 25 μL per well of Hexyl Dye Solution into cell plates.Incubate for 20-35 minutes at room temp or ambient conditions.

5) Dispense 80 μL per well of Bathl into compound plates. Acid Yellow-17(1 mM) is added and Potassium Chloride can be altered from 4.5 to 20 mMdepending on the NaV subtype and assay sensitivity.

6) Wash cell plates three times with 100 μL per well of Bathl, leaving25 μL of residual volume. Then transfer 25 uL per well from CompoundPlates to Cell Plates. Incubate for 20-35 minutes at room temp/ambientcondition

7) Read Plate on E-VIPR. Use the current-controlled amplifier to deliverstimulation wave pulses for typically 9 seconds and a scan rate of 400Hz. A pre-stimulus recording is performed for 0.5 seconds to obtain theun-stimulated intensities baseline. The stimulatory waveform is appliedfor 9 seconds followed by 0.5 seconds of post-stimulation recording toexamine the relaxation to the resting state. The stimulatory waveform ofthe electrical stimulation is specific for each cell type and can varythe magnitude, duration and frequency of the applied current to providean optimal assay signal.

Data Analysis

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu} {nm}} - {background}_{460\mspace{14mu} {nm}}} \right)}{\left( {{intensity}_{580\mspace{14mu} {nm}} - {background}_{580\mspace{14mu} {nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R═R_(f)/R_(i) is thencalculated and reported as a function of time.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$

where R is the ratio response of the test compound

Electrophysiology Assays for NaV Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy andselectivity of sodium channel blockers in dorsal root ganglion neurons.Rat neurons were isolated from the dorsal root ganglions and maintainedin culture for 2 to. 10 days in the presence of NGF (50 ng/ml) (culturemedia consisted of NeurobasalA supplemented with B27, glutamine andantibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter)have been visually identified and probed with fine tip glass electrodesconnected to an amplifier (Axon Instruments). The “voltage clamp” modehas been used to assess the compound's IC50 holding the cells at −60 mV.In addition, the “current clamp” mode has been employed to test theefficacy of the compounds in blocking action potential generation inresponse to current injections. The results of these experiments havecontributed to the definition of the efficacy profile of the compounds.

IonWorks Assays.

Sodium currents were recorded using the automated patch clamp system,IonWorks (Molecular Devices Corporation, Inc.). Cells expressing Navsubtypes are harvested from tissue culture and placed in suspension at0.5-4 million cells per mL Bath1. The IonWorks instrument measureschanges in sodium currents in response to applied voltage clampsimilarly to the traditional patch clamp assay, except in a 384-wellformat. Using the Ion Works, dose-response relationships were determinedin voltage clamp mode by depolarizing the cell from the experimentspecific holding potential to a test potential of about 0 mV before andfollowing addition of the test compound. The influence of the compoundon currents are measured at the test potential.

1-Benzazepin-2-one Binding Assay

The sodium channel inhibiting properties of the compounds of theinvention can also be determined by assay methods described in Williams,B. S. et al., “Characterization of a New Class of Potent Inhibitors ofthe Voltage-Gated Sodium Channel NaV 1.7,” Biochemistry, 2007, 46,14693-14703, the entire contents of which are incorporated herein byreference.

The exemplified compounds of Table 1 herein are active against one ormore sodium channels as measured using the assays described herein aboveas presented in Table 3.

TABLE 3 IC50: +++ <= 2.0 μM ++ <= 5.0 μM < + Cmpd. Binned Activity No.Data 1 2 + 3 +++ 4 +++ 5 +++ 6 7 +++ 8 ++ 9 +++ 10 11 +++ 12 ++ 13 +++14 +++ 15 + 16 +++ 17 ++ 18 19 20 21 +++ 22 ++ 23 +++ 24 +++ 25 26 +++27 +++ 28 ++ 29 +++ 30 +++ 31 +++ 32 +++ 33 34 +++ 35 36 +++ 37 +++ 38+++ 39 +++ 40 ++ 41 +++ 42 +++ 43 ++ 44 +++ 45 +++ 46 + 47 +++ 48 +++49 + 50 +++ 51 +++ 52 +++ 53 +++ 54 +++ 55 +++ 56 +++ 57 +++ 58 59 +++60 +++ 61 62 +++ 63 +++ 64 65 +++ 66 +++ 67 +++ 68 69 +++ 70 +++ 71 7273 74 +++ 75 76 +++ 77 78 +++ 79 80 + 81 +++ 82 +++ 83 +++ 84 ++ 85 8687 + 88 89 90 +++ 91 92 ++ 93 ++ 94 +++ 95 +++ 96 97 +++ 98 +++ 99 +++100 101 +++ 102 + 103 +++ 104 + 105 +++ 106 +++ 107 108 +++ 109 +++ 110111 +++ 112 +++ 113 +++ 114 +++ 115 +++ 116 +++ 117 +++ 118 119 ++ 120121 +++ 122 123 +++ 124 125 +++ 126 +++ 127 + 128 +++ 129 +++ 130 +++131 +++ 132 133 134 135 +++ 136 137 + 138 +++ 139 +++ 140 +++ 141 +++142 +++ 143 ++ 144 145 +++ 146 +++ 147 +++ 148 149 150 + 151 +++ 152 153+++ 154 +++ 155 +++ 156 +++ 157 158 +++ 159 +++ 160 + 161 +++ 162 163164 +++ 165 +++ 166 +++ 167 +++ 168 +++ 169 ++ 170 +++ 171 +++ 172 +++173 +++ 174 +++ 175 +++ 176 +++ 177 178 179 180 +++ 181 +++ 182 ++ 183+++ 184 +++ 185 186 +++ 187 +++ 188 +++ 189 +++ 190 +++ 191 +++ 192 193+++ 194 +++ 195 +++ 196 +++ 197 +++ 198 +++ 199 +++ 200 +++ 201 202 +++203 +++ 204 205 +++ 206 +++ 207 +++ 208 +++ 209 +++ 210 211 +++ 212 +++213 +++ 214 + 215 +++ 216 +++ 217 ++ 218 +++ 219 +++ 220 +++ 221 222 +++223 +++ 224 +++ 225 226 227 ++ 228 +++ 229 230 +++ 231 + 232 233 ++ 234235 +++ 236 + 237 +++ 238 +++ 239 +++ 240 ++ 241 + 242 + 243 +++ 244 245++ 246 +++ 247 +++ 248 249 +++ 250 ++ 251 +++ 252 ++ 253 +++ 254 255 +++256 +++ 257 +++ 258 +++ 259 +++ 260 ++ 261 262 +++ 263 +++ 264 265 +++266 267 +++ 268 269 +++ 270 +++ 271 + 272 + 273 274 +++ 275 276 +++ 277+++ 278 279 +++ 280 281 +++ 282 +++ 283 +++ 284 +++ 285 +++ 286 +++ 287+++ 288 289 +++ 290 +++ 291 +++ 292 +++ 293 +++ 294 295 +++ 296 +++ 297+++ 298 +++ 299 + 300 +++ 301 302 303 +++ 304 +++ 305 +++ 306 +++ 307+++ 308 +++ 309 + 310 +++ 311 +++ 312 +++ 313 +++ 314 +++ 315 +++ 316+++ 317 + 318 +++ 319 ++ 320 321 +++ 322 ++ 323 ++ 324 + 325 ++ 326 +++327 +++ 328 +++ 329 330 +++ 331 + 332 333 +++ 334 + 335 336 +++ 337 +++338 +++ 339 340 +++ 341 + 342 +++ 343 + 344 345 +++ 346 +++ 347 +++ 348+++ 349 +++ 350 +++ 351 352 +++ 353 + 354 355 +++ 356 357 +++ 358 ++ 359+++ 360 +++ 361 +++ 362 +++ 363 +++ 364 +++ 365 366 +++ 367 +++ 368 369+++ 370 +++ 371 372 +++ 373 +++ 374 375 +++ 376 +++ 377 +++ 378 +++ 379+++ 380 381 +++ 382 +++ 383 +++ 384 + 385 386 387 +++ 388 +++ 390 391 ++392 +++ 393 +++ 394 395 +++ 396 +++ 397 398 ++ 399 +++ 400 401 +++ 402403 +++ 404 +++ 405 + 406 +++ 407 +++ 408 ++ 409 + 410 +++ 411 + 412 413+++ 414 +++ 415 +++ 416 +++ 417 +++ 418 ++ 419 +++ 420 +++ 421 422 ++423 +++ 424 +++ 425 + 426 +++ 427 +++ 428 429 +++ 430 +++ 431 +++ 432433 +++ 434 +++ 435 +++ 436 +++ 437 +++ 438 +++ 439 +++ 440 +++ 441 442+++ 443 +++ 444 + 445 ++ 446 +++ 447 +++ 448 ++ 449 +++ 450 451 452 +++453 +++ 454 ++ 455 + 456 +++ 457 458 459 460 +++ 461 462 ++ 463 +++ 464+++ 465 +++ 466 +++ 467 468 +++ 469 ++ 470 ++ 471 472 +++ 473 +++ 474 ++475 +++ 476 +++ 477 +++ 478 +++ 479 + 480 +++ 481 + 482 483 +++ 484 +++485 +++ 486 +++ 487 +++ 488 489 ++ 490 +++ 491 + 492 493 494 +++ 495 +++496 + 497 +++ 498 499 ++ 500 +++ 501 +++ 502 +++ 503 +++ 504 +++ 505 ++506 +++ 507 + 508 +++ 509 +++ 510 511 +++ 512 +++ 513 +++ 514 +++ 515+++ 516 +++ 517 +++ 518 +++ 519 +++ 520 521 +++ 522 +++ 523 +++ 524 +++525 +++ 526 527 528 +++ 529 +++ 530 +++ 531 +++ 532 +++ 533 +++ 534 +++535 +++ 536 +++ 537 +++ 538 +++ 539 540 ++ 541 +++ 542 ++ 543 +++ 544+++ 545 546 +++ 547 +++ 548 549 +++ 550 ++ 551 +++ 552 +++ 553 ++ 554+++ 555 +++ 556 ++ 557 +++ 558 +++ 559 +++ 560 561 +++ 562 +++ 563 564++ 565 566 + 567 +++ 568 +++ 569 + 570 +++ 571 +++ 572 ++ 573 +++ 574+++ 575 576 +++ 577 578 +++ 579 +++ 580 +++ 581 +++ 582 +++ 583 +++ 584585 ++ 586 + 587 +++ 588 +++ 589 +++ 590 +++ 591 592 +++ 593 +++ 594 +++595 +++ 596 +++ 597 598 +++ 599 +++ 600 +++ 601 +++ 602 +++ 603 604 605+++ 606 +++ 607 ++ 608 +++ 609 +++ 610 +++ 611 +++ 612 +++ 613 +++ 614++ 615 616 617 +++ 618 +++ 619 + 620 +++ 621 +++ 622 +++ 623 +++ 624 625626 +++ 627 +++ 628 +++ 629 630 631 +++ 632 +++ 633 +++ 634 635 +++ 636+++ 637 +++ 638 639 640 +++ 641 642 ++ 643 ++ 644 + 645 646 +++ 647 648649 650 +++ 651 +++ 652 +++ 653 +++ 654 655 +++ 656 657 + 658 +++ 659 +660 +++ 661 662 ++ 663 +++ 664 +++ 665 +++ 666 ++ 667 + 668 +++ 669 +++670 + 671 +++ 672 +++ 673 +++ 674 ++ 675 +++ 676 677 +++ 678 +++ 679 ++680 +++ 681 +++ 682 +++ 683 +++ 684 +++ 685 ++ 686 +++ 687 +++ 688 +++689 +++ 690 ++ 691 692 693 +++ 694 +++ 695 696 697 +++ 698 +++ 699 +++700 +++ 701 ++ 702 ++ 703 +++ 704 +++ 705 +++ 706 +++ 707 708 709 +++710 +++ 711 +++ 712 713 +++ 714 ++ 715 716 +++ 717 718 ++ 719 720 721+++ 722 +++ 723 +++ 724 +++ 725 +++ 726 +++ 727 +++ 728 +++ 729 +++ 730731 732 +++ 733 ++ 734 +++ 735 +++ 736 + 737 +++ 738 ++ 739 +++ 740 +++741 ++ 742 ++ 743 744 +++ 745 +++ 746 ++ 747 + 748 ++ 749 750 +++ 751+++ 752 +++ 753 754 + 755 +++ 756 757 758 +++ 759 +++ 760 761 +++ 762+++ 763 ++ 764 +++ 765 +++ 766 767 +++ 768 +++ 769 +++ 770 +++ 771 +++772 +++ 773 +++ 774 +++ 775 776 777 +++ 778 +++ 779 780 781 ++ 782 +++783 784 +++ 785 +++ 786 787 788 +++ 789 + 790 +++ 791 +++ 792 +++ 793+++ 794 + 795 796 +++ 797 +++ 798 799 +++ 800 801 +++ 802 803 804 + 805+++ 806 807 + 808 +++ 809 810 +++ 811 + 812 +++ 813 814 + 815 +++ 816817 +++ 818 +++ 819 +++ 820 +++ 821 +++ 822 +++ 823 824 +++ 825 826 +++827 828 +++ 829 830 +++ 831 +++ 832 + 833 +++ 834 +++ 835 836 +++ 837+++ 838 ++ 839 +++ 840 +++ 841 +++ 842 + 843 ++ 844 +++ 845 +++ 846 +++847 +++ 848 +++ 849 + 850 851 +++ 852 +++ 853 +++ 854 ++ 855 +++ 856 +++857 +++ 858 +++ 859 ++ 860 +++ 861 +++ 862 +++ 863 +++ 864 +++ 865 866+++ 867 +++ 868 ++ 869 +++ 870 +++

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

We claim:
 1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence and optionally substituted as valency allows: R¹ isC1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, N(R⁷)₂,NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂,SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl, heteroaryl or(C1-C6)-R⁸ wherein up to two CH₂ units may be replaced with O, CO, S,SO, SO₂, NR⁷; R² is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl,halo, aryl, an electron withdrawing group, CH₂CF₃, CHF₂, CF₃, CN, OH,OR⁷, CON(R⁷)₂, SO₂R⁷, SR⁷, SOR⁷, SO₂N(R⁷)₂, or (C1-C6)-R⁸ wherein up totwo CH₂ units may be replaced with O, CO, S, SO, SO₂, CF₂, or NR⁷; R³ ishalo, C1-C6 alkyl or C3-C8 cycloalkyl, wherein up to two CH₂ units maybe replaced by O, CO, S, SO, SO₂, or NR⁸, or 2 occurrences of R³ takentogether form a C3-C8 cycloalkyl group; R⁷ is H, C1-C6 alkyl, CHF₂, CF₃,or C3-C8 cycloalkyl, or 2 R⁷ taken together with the atoms to which theyare attached form a ring; R⁸ is H, CF₃, CO₂R⁷, OH, aryl, heteroaryl,C3-C8 cycloalkyl, heterocycloalkyl, N(R⁷)₂, NR⁷COR⁷, CON(R⁷)₂, CN, orSO₂R⁷; A is aryl, heteroaryl or heterocyclic; X is N, S, or CR² whereinat least one X is N; W is N or CH, wherein up to 2 W are N; a ---- linedenotes an optionally double bond depending on the identity of X; m isan integer from 0 to 4 inclusive; n is an integer from 0 to 3 inclusive;and o is an integer from 0 to 4 inclusive.
 2. The compound of claim 1,wherein all W's are CH.
 3. The compound of claim 1, wherein one W is N.4. The compound of claim 1, wherein R¹ is C1-C6 alkyl, C1-C6 alkoxy,halo, CN, CON(R⁷)₂, or (C1-C6)-R⁸ wherein up to two CH₂ units may bereplaced with O or NR⁷.
 5. The compound of claim 1, wherein R¹ is F, Cl,CH₃, CN, OCH₃, CH₂OH, CH₂N(CH₃)₂, CH₂NH₂, CONHCH₃, CON(CH₃)₂, CH₂OCH₃.6. The compound of claim 1, wherein R² is C1-C6 alkyl, C1-C6 haloalkyl,halo, CN, CF₃, CON(R⁷)₂, SO₂R⁷, or (C1-C6)-R⁸ wherein up to two CH₂units may be replaced with O, CO, S, SO, SO₂, CF₂, or NR⁷.
 7. Thecompound of claim 1, wherein R² is CH₃, CF₃, CHF₂, C₂H₅, CH₂OH, F, CN,(CH₂)₂OCH₃, SO₂CH₃, SOCH₃, CH₂CF₃, CH₂NH₂, CH₂NHCOCH₃, CH₂NHCOH, COCH₃,or CONHCH₃.
 8. The compound of claim 1, wherein R³ is C1-C6 alkyl. 9.The compound of claim 1, wherein R³ is methyl.
 10. The compound of claim1, wherein 2 occurrences of R³ taken together form a C3-C8 cycloalkylgroup.
 11. The compound of claim 1, wherein A is

wherein: R⁴ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN,OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷,CON(R⁷)₂, SO₂N(R⁷)₂, CHF₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl,heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R⁸ whereinup to three CH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁷; R⁵is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy,halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷, CO₂R⁷, NR⁷COR⁷,NR⁷CO₂R⁷, CON(R⁷)₂, SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl,heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R⁸ whereinup to three CH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁷; R⁶is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷,N(R⁷)₂, NR⁷SO₂R⁷, SR⁷, SOR⁷, SO₂R⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂,SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl, heteroaryl, or astraight chain, branched, or cyclic (C1-C8)-R⁸ wherein up to three CH₂units may be replaced with O, CO, S, SO, SO₂, or NR⁷; or two occurrencesof R⁴ and R⁵, or R⁵ and R⁶ are both C1-C6 alkyl and together with thecarbons to which they are attached form an optionally substituted ringcomprising up to 2 heteroatoms.
 12. The compound of claim 11, wherein R⁴is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, CON(R⁷)₂, NR⁷SO₂R⁷,SO₂R⁷, SOR⁷, SR⁷, CO₂R⁷, NR⁷CO₂R⁷, CHF₂, CF₃, OCF₃, OCHF₂, heteroaryl,or a straight chain, branched, or cyclic (C1-C8)-R⁸ wherein up to threeCH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁷.
 13. Thecompound of claim 11, wherein R⁴ is H, F, Cl, OH, CH₃, CHF₂, CF₃, OCH₃,OCHF₂, OCF₃, SO₂CH₃, CN, NHSO₂CH₃, C₂H₅, OC₂H₅, OCF₂CHFC1, OCH₂CF₃,O(CH₂)₂CH₃, OCH(CH₃)₂, O(CH₂)₂OH, OCH₂OCH₃, CO₂CH₃, CH₂OH, SCH₃,CON(CH₃)₂, NHCO₂tBu,


14. The compound of claim 11, wherein R⁵ is H, C1-C6 alkyl, C1-C6alkoxy, halo, CN, OH, OR⁷, NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷, CO₂R⁷, CON(R⁷)₂,SO₂N(R⁷)₂, CF₃, OCF₃, or a straight chain, branched, or cyclic(C1-C8)-R⁸ wherein up to three CH₂ units may be replaced with O, CO, S,SO, SO₂, or NR⁷.
 15. The compound of claim 11, wherein R⁵ is H, F, Cl,CH₃, C₂H₅, CH(CH₃)₂, tBu, OH, OCH₃, OC₂H₅, OCH(CH₃)₂, CH₂OH, CF₃, OCF₃,CN, CO₂CH₃, CONH₂, N(CH₃)SO₂CH₃, SO₂NH₂ or SO₂CH₃.
 16. The compound ofclaim 11, wherein R⁶ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy,halo, CN, OH, OR⁷, SR⁷, SOR⁷, SO₂R⁷, NR⁷COR⁷, SO₂N(R⁷)₂, CON(R⁷)₂, CF₃,OCF₃, OCHF₂, heterocycloalkyl, heteroaryl or a straight chain, branched,or cyclic (C1-C8)-R⁸ wherein up to three CH₂ units may be replaced withO, CO, S, SO, SO₂, or NR⁷.
 17. The compound of claim 11, wherein R⁶ isH, F, Cl, CH₃, CF₃, OCH₃, OC₂H₅, CH₂CH₂OH, OCF₃, OCHF₂, SOCH(CH₃)₂,SO₂CH₃, SO₂CH(CH₃)₂, SO₂CHF₂, SO₂CF₃, SO₂C₂H₅, SO₂CH₂CH(CH₃)₂, SO₂tBu,OH, CN, CH₂CH₃, OCH₂CF₃, O(CH₂)₂OH, NHC(═O)CH₃, OCH₂C(═O)NH₂,

O(CH₂)₂CH₃,

O(CH₂)₃OH, O(CH₂)₂OCH₃,

O(CH₂)₂OCF₃,

O(CH₂)₂SO₂CH₃, tBu,

OtBu,

O(CH₂)₃OCH₃, O(CH₂)₂OC₂H₅,

O(CH₂)₂N(CH₃)₂,

OCH₂Ph, SO₂NHCH₃, SO₂N(CH₃)₂, SO₂NHCH₂CH₃, SO₂N(CH₃)CH(CH₃)₂,SO₂CH₂CH₂OH, CONHCH(CH₃)₂ or OCH₂CO₂H.
 18. The compound of claim 11,wherein two occurrences of R⁴ and R⁵ are both C1-C6 alkyl and togetherwith the carbons to which they are attached form an optionallysubstituted ring comprising up to 2 heteroatoms.
 19. The compound ofclaim 11, wherein two occurrences of R⁵ and R⁶ are C1-C6 alkyl andtogether with the carbons to which they are attached form an optionallysubstituted ring comprising up to 2 heteroatoms.
 20. The compound ofclaim 11, wherein R⁴ is H.
 21. The compound of claim 11, wherein R⁵ ishalo, CF₃, C1-C6 alkyl, or C1-C6 alkoxy.
 22. The compound of claim 11,wherein R⁵ is C1-C6 alkoxy.
 23. The compound of claim 11, wherein R⁶ isC1-C6 alkyl or C1-C6 alkoxy.
 24. The compound of claim 11, wherein R⁶ isC1-C6 alkyl.
 25. The compound of claim 11, wherein R⁴ is H or alkoxy; R⁵is H, halo, CF₃, C1-C6 alkyl, or C1-C6 alkoxy; and R⁶ is H, (C1-C6)-R⁸wherein two methylene units have been replaced with O, or SO₂R⁷.
 26. Thecompound of claim 11, wherein R⁴ is H or OCHF₂, and R⁵ and R⁶ are H. 27.The compound of claim 11, wherein R⁴ and R⁵ are H, and R⁶ is (C1-C6)-R⁸wherein two methylene units have been replaced with O.
 28. The compoundof claim 11, wherein R⁴ is halo, R⁵ is H, and R⁶ is alkoxy.
 29. Thecompound of claim 11, wherein R⁴ and R⁵ are H, and R⁶ is SO₂R⁷.
 30. Thecompound of claim 11, wherein

is selected from:


31. The compound of claim 1, wherein A is heteroaryl or heterocyclic.32. The compound of claim 31, wherein A is selected from:


33. The compound of claim 1, wherein the compound has formula IA:

wherein: R⁴ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN,OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷,CON(R⁷)₂, SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl,heteroaryl or a straight chain, branched, or cyclic (C1-C8)-R⁸ whereinup to three CH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁷; R⁵is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy,halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷, CO₂R⁷, NR⁷COR⁷,NR⁷CO₂R⁷, CON(R⁷)₂, SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl,heteroaryl or a straight chain, branched, or cyclic (C1-C8)-R⁸ whereinup to three CH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁷; R⁶is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷,N(R⁷)₂, NR⁷SO₂R⁷, SOW, SO₂R⁷, SR⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂,SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl, heteroaryl or astraight chain, branched, or cyclic (C1-C8)-R⁸ wherein up to three CH₂units may be replaced with O, CO, S, SO, SO₂, or NR⁷; or two occurrencesof R⁴ and R⁵, or R⁵ and R⁶ are both C1-C6 alkyl and together with thecarbons to which they are attached form an optionally substituted ringcomprising up to 2 heteroatoms.
 34. The compound of claim 33, wherein R¹is C1-C6 alkyl, C1-C6 alkoxy, halo, CN, CON(R⁷)₂, or (C1-C6)-R⁸ whereinup to two CH₂ units may be replaced with O or NR⁷
 35. The compound ofclaim 33, wherein R¹ is F, Cl, CN, CH₃, CH₂OH, CH₂N(CH₃)₂, CH₂NH₂,CONHCH₃, CON(CH₃)₂, CH₂OCH₃.
 36. The compound of claim 33, wherein R² isC1-C6 alkyl, CN, CF₃, CON(R⁷)₂, SO₂R⁷, or (C1-C6)-R⁸ wherein up to twoCH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁷.
 37. Thecompound of claim 33, wherein R² is CH₃, CF₃, CH₂OH, CN, SO₂CH₃, SOCH₃,CH₂NH₂, CH₂NHCOCH₃, CH₂NHCOH, COCH₃, or CONHCH₃.
 38. The compound ofclaim 33, wherein R³ is C1-C6 alkyl or 2 occurrences of R³ takentogether form a C3-C8 cycloalkyl group.
 39. The compound of claim 33,wherein R³ is CH₃.
 40. The compound of claim 33, wherein 2 occurrencesof R³ taken together form a C3-C8 cycloalkyl group.
 41. The compound ofclaim 33, wherein R⁴ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷,CHF₂, CF₃, OCF₃, OCHF₂, SO₂R⁷, SR⁷, SOR⁷⁻, NR⁷CO₂R⁷, heteroaryl, or astraight chain, branched, or cyclic (C1-C8)-R⁸ wherein up to three CH₂units may be replaced with O, CO, S, SO, SO₂, or NR⁷.
 42. The compoundof claim 33, wherein R⁴ is H, F, Cl, OH, CH₃, CHF₂, CF₃, OCH₃, OCHF₂,OCF₃, CO₂CH₃, CH₂OH, SO₂CH₃, CN, NHCO₂tBu, C₂H₅, OCF₂CHFCl,


43. The compound of claim 33, wherein R⁵ is H, C1-C6 alkyl, C1-C6alkoxy, halo, CN, OH, OR⁷, NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOW, CO₂R⁷, CON(R⁷)₂,SO₂N(R⁷)₂, CF₃, OCF₃, or a straight chain, branched, or cyclic(C1-C8)-R⁸ wherein up to three CH₂ units may be replaced with O, CO, S,SO, SO₂, or NR⁷.
 44. The compound of claim 33, wherein R⁵ is H, F, Cl,CH₃, C₂H₅, tBu, OH, OCH₃, OC₂H₅, OCH(CH₃)₂, CH₂OH, CF₃, OCF₃, CN,CO₂CH₃, CONH₂, N(CH₃)SO₂CH₃, SO₂NH₂ or SO₂CH₃.
 45. The compound of claim33, wherein R⁶ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo,CN, OH, OR⁷, SO₂R⁷, SR⁷, SOR⁷, NR⁷COR⁷, SO₂N(R⁷)₂, CF₃, OCF₃,heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R⁸, whereinup to three CH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁷.46. The compound of claim 33, wherein R⁶ is H, F, CH₃, CF₃, OCH₃, OCF₃,SO₂CH₃, SO₂C₂H₅, SO₂CH(CH₃)₂, SO₂CH₂CH(CH₃)₂, SO₂tBu, SO₂CHF₂, CN,CH₂CH₃, tBu, CH₂CH₂OH, C(CH₃)₂OH, OCH₂CF₃, O(CH₂)₂OH, NHC(═O)CH₃,OCH₂C(═O)NH₂,

O(CH₂)₂CH₃,

O(CH₂)₃OH, O(CH₂)₂OCH₃,

O(CH₂)₂OCF₃,

O(CH₂)₂SO₂CH₃,

OtBu,

O(CH₂)₃OCH₃, O(CH₂)₂OC₂H₅,

O(CH₂)₂N(CH₃)₂,

OCH₂Ph, SO₂NHCH₃, SO₂NHCH₂CH₃, SO₂CH₂CH₂OH or OCH₂CO₂H.
 47. The compoundof claim 33, wherein o is 2, and the two occurrences of R³ form a C3-C8cycloalkyl group.
 48. The compound of claim 33, wherein

is selected from:


49. The compound of claim 1, wherein the compound has formula IB:

wherein: R⁴ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN,OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷,CON(R⁷)₂, SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl,heteroaryl or a straight chain, branched, or cyclic (C1-C8)-R⁸ whereinup to three CH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁷; R⁵is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy,halo, CN, OH, OR⁷, N(R⁷)₂, NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷, CO₂R⁷, NR⁷COR⁷,NR⁷CO₂R⁷, CON(R⁷)₂, SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl,heteroaryl or a straight chain, branched, or cyclic (C1-C8)-R⁸ whereinup to three CH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁷; R⁶is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷,N(R⁷)₂, NR⁷SO₂R⁷, SOW, SO₂R⁷, SR⁷, CO₂R⁷, NR⁷COR⁷, NR⁷CO₂R⁷, CON(R⁷)₂,SO₂N(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, aryl, heteroaryl or astraight chain, branched, or cyclic (C1-C8)-R⁸ wherein up to three CH₂units may be replaced with O, CO, S, SO, SO₂, or NR⁷; or two occurrencesof R⁴ and R⁵, or R⁵ and R⁶ are both C1-C6 alkyl and together with thecarbons to which they are attached form an optionally substituted ringcomprising up to 2 heteroatoms.
 50. The compound of claim 49, wherein R¹is halo or C1-C6 alkoxy.
 51. The compound of claim 49, wherein R¹ is F,Cl or OCH₃.
 52. The compound of claim 49, wherein R² is C1-C6 alkyl, CF₃or (C1-C6)-R⁸ wherein up to two CH₂ units may be replaced with O, CO, S,SO, SO₂, or NR⁷.
 53. The compound of claim 49, wherein R² is CH₃, CF₃,C₂H₅, CH(CH₃)₂, CH₂CF₃, or (CH₂)₂OCH₃.
 54. The compound of claim 49,wherein R⁴ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, CON(R⁷)₂,NR⁷SO₂R⁷, SO₂R⁷, SR⁷, SOR⁷, CO₂R⁷, NR⁷CO₂R⁷, CHF₂, CF₃, OCF₃, OCHF₂,heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R⁸ whereinup to three CH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁷.55. The compound of claim 49, wherein R⁴ is H, F, Cl, OH, CH₃, CHF₂,CF₃, OCH₃, OCHF₂, OCF₃, SO₂CH₃, CN, NHSO₂CH₃, C₂H₅, OC₂H₅, OCF₂CHFC1,OCH₂CF₃, O(CH₂)₂CH₃, OCH₂OCH₃, OCH(CH₃)₂, O(CH₂)₂OH, SCH₃, CON(CH₃)₂,NHCO₂tBu,


56. The compound of claim 49, wherein R⁵ is H, C1-C6 alkyl, C1-C6alkoxy, halo, CN, OH, OR⁷, CF₃, OCF₃, SO₂R⁷, SOR⁷, or a straight chain,branched, or cyclic (C1-C8)-R⁸ wherein up to three CH₂ units may bereplaced with O, CO, S, SO, SO₂, or NR⁷.
 57. The compound of claim 49,wherein R⁵ is H, F, Cl, CH₃, CF₃, OCH₃, CH(CH₃)₂, OCH₂CH₃, CH₂OH, OCF₃,CN, SO₂CH₃ or tBu.
 58. The compound of claim 49, wherein R⁶ is H, C1-C6alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, OH, OR⁷, SOR⁷, SO₂R⁷, SR⁷,SO₂N(R⁷)₂, CON(R⁷)₂, CF₃, OCF₃, OCHF₂, heterocycloalkyl, heteroaryl, astraight chain, branched, or cyclic (C1-C8)-R⁸, wherein up to three CH₂units may be replaced with O, CO, S, SO, SO₂, or NR⁷.
 59. The compoundof claim 49, wherein R⁶ is H, F, Cl, OH, CH₃, CF₃, OCH₃, OCF₃, OCHF₂,SOCH(CH₃)₂, SO₂CH₃, SO₂CHF₂, SO₂CF₃, SO₂C₂H₅, SO₂CH(CH₃)₂,SO₂CH₂CH(CH₃)₂, SO₂tBu, SO₂NHCH₃, SO₂N(CH₃)₂, SO₂NHCH₂CH₃,SO₂N(CH₃)CH(CH₃)₂, CONHCH(CH₃)₂, CH₂CH₃, OCH₂CH₃,

O(CH₂)₂CH₃,

O(CH₂)₂OCH₃, O(CH₂)₂OCF₃, tBu,

OtBu

or OCH₂Ph.
 60. The compound of claim 49, wherein two occurrences of R⁴and R⁵ are both C1-C6 alkyl and together with the carbons to which theyare attached form an optionally substituted ring comprising up to 2heteroatoms.
 61. The compound of claim 49, wherein two occurrences of R⁵and R⁶ are both C1-C6 alkyl and together with the carbons to which theyare attached form an optionally substituted ring comprising up to 2heteroatoms.
 62. The compound of claim 49, wherein

is selected from:


63. The compound of claim 1, wherein the compound is selected fromTable
 1. 64. A pharmaceutical composition comprising the compound ofclaim 1 and a pharmaceutically acceptable carrier.
 65. A method ofinhibiting a voltage-gated sodium ion channel in: (a) a patient; or (b)a biological sample; comprising administering to the patient, orcontacting the biological sample, with the compound of claim
 1. 66. Themethod of claim 65, wherein the voltage-gated sodium ion channel is NaV1.7.
 67. A method of treating or lessening the severity in a subject ofacute, chronic, neuropathic, or inflammatory pain, arthritis, migraine,cluster headaches, trigeminal neuralgia, herpatic neuralgia, generalneuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders, anxiety, depression, dipolar disorder,myotonia, arrhythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, cancer pain, stroke, cerebral ischemia, traumaticbrain injury, amyotrophic lateral sclerosis, stress- or exercise inducedangina, palpitations, hypertension, migraine, or abormalgastro-intestinal motility, comprising administering an effective amountof a compound of claim
 1. 68. The method according to claim 67, whereinsaid method is used for treating or lessening the severity of femurcancer pain; non-malignant chronic bone pain; rheumatoid arthritis;osteoarthritis; spinal stenosis; neuropathic low back pain; neuropathiclow back pain; myofascial pain syndrome; fibromyalgia; temporomandibularjoint pain; chronic visceral pain, abdominal pain; pancreatic; IBS pain;chronic and acute headache pain; migraine; tension headache, including,cluster headaches; chronic and acute neuropathic pain, post-herpaticneuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminalneuralgia; Charcot-Marie Tooth neuropathy; hereditary sensoryneuropathies; peripheral nerve injury; painful neuromas; ectopicproximal and distal discharges; radiculopathy; chemotherapy inducedneuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomypain; central pain; spinal cord injury pain; post-stroke pain; thalamicpain; complex regional pain syndrome; phantom pain; intractable pain;acute pain, acute post-operative pain; acute musculoskeletal pain; jointpain; mechanical low back pain; neck pain; tendonitis; injury/exercisepain; acute visceral pain, abdominal pain; pyelonephritis; appendicitis;cholecystitis; intestinal obstruction; hernias; chest pain, cardiacpain; pelvic pain, renal colic pain, acute obstetric pain, labor pain;cesarean section pain; acute inflammatory, burn and trauma pain; acuteintermittent pain, endometriosis; acute herpes zoster pain; sickle cellanemia; acute pancreatitis; breakthrough pain; orofacial pain includingsinusitis pain, dental pain; multiple sclerosis (MS) pain; pain indepression; leprosy pain; Behcet's disease pain; adiposis dolorosa;phlebitic pain; Guillain-Barre pain; painful legs and moving toes;Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladderand urogenital disease, including, urinary incontinence; hyperactivitybladder; painful bladder syndrome; interstitial cyctitis (IC);prostatitis; complex regional pain syndrome (CRPS), type I and type II;widespread pain, paroxysmal extreme pain, pruritis, tinnitis, orangina-induced pain.